Cyclic amides

ABSTRACT

Cyclic amides are inhibitors of tumor necrosis factor and can be used to combat cachexia, endotoxic shock, and retrovirus replication. A typical embodiment is 3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of Ser. No. 08/703,708 filed Aug. 27, 1996, now U.S.Pat. No. 5,698,579, which is a continuation-in-part of Ser. No.08/258,587 filed Jun. 10, 1994, now U.S. Pat. No. 5,605,914, which inturn is a continuation-in-part of Ser. No. 08/087,510 filed Jul. 2,1993, now abandoned, and Ser. No. 08/140,237 filed Oct. 20, 1993, nowU.S. Pat. No. 5,463,063, the disclosures of which are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

The present invention relates a method of reducing levels of TNFα in amammal and to compounds and compositions useful therein.

TNFα, or tumor necrosis factor α, is a cytokine which is releasedprimarily by mononuclear phagocytes in response to variousimmunostimulators. When administered to animals or humans it causesinflammation, fever, cardiovascular effects, hemorrhage, coagulation,and acute phase responses similar to those seen during acute infectionsand shock states.

Excessive or unregulated TNFα production has been implicated in a numberof disease conditions. These include endotoxemia and toxic shocksyndrome {Tracey et al., Nature 330, 662-664 (1987) and Hinshaw et al.,Circ. Shock 30,279-292 (1990)}; cachexia {Dezube et al., Lancet, 335(8690), 662 (1990)} and Adult Respiratory Distress Syndrome where TNFαconcentration in excess of 12,000 pg/mL have been detected in pulmonaryaspirates from ARDS patients {Millar et al., Lancet 2(8665), 712-714(1989)}. Systemic infusion of recombinant TNFα also resulted in changestypically seen in ARDS {Ferrai-Baliviera et al., Arch. Surg. 124(12),1400-1405 (1989)}.

TNFα appears to be involved in bone resorption diseases, includingarthritis where it has been determined that when activated, leukocyteswill produce a bone-resorbing activity, and data suggest that TNFαcontributes to this activity. {Bertolini et al., Nature 319, 516-518(1986) and Johnson et al., Endocrinology 124(3), 1424-1427 (1989).} TNFαhas been shown to stimulate bone resorption and inhibit bone formationin vitro and in vivo through stimulation of osteoclast formation andactivation combined with inhibition of osteoblast function. AlthoughTNFα may be involved in many bone resorption diseases, includingarthritis, the most compelling link with disease is the associationbetween production of TNFα by tumor or host tissues and malignancyassociated hypercalcemia {Calci. Tissue Int. (US) 46(Suppl.), S3-10(1990)}. In Graft versus Host Reaction, increased serum TNFα levels havebeen associated with major complication following acute allogenic bonemarrow transplants {Holler et al., Blood, 75(4), 1011-1016 (1990)}.

Cerebral malaria is a lethal hyperacute neurological syndrome associatedwith high blood levels of TNFα. Levels of serum TNFα correlated directlywith the severity of disease and the prognosis in patients with acutemalaria attacks {Grau et al., N. Engl. J Med. 320(24), 1586-1591(1989)}.

TNFα plays a role in the area of chronic pulmonary inflammatorydiseases. The deposition of silica particles leads to silicosis, adisease of progressive respiratory failure caused by a fibroticreaction. Antibody to TNFα completely blocked the silica-induced lungfibrosis in mice {Pignet et al., Nature, 344:245-247 (1990)}. Highlevels of TNFα production (in the serum and in isolated macrophages)have been demonstrated in animal models of silica and asbestos inducedfibrosis {Bissonnette et al., Inflammation 13(3), 329-339 (1989)}.Alveolar macrophages from pulmonary sarcoidosis patients have also beenfound to spontaneously release massive quantities of TNFα as comparedwith macrophages from normal donors {Baughman et al., J Lab. Clin. Med.115(1), 36-42 (1990)}.

TNFα is implicated in the inflammatory response which followsreperfusion, called reperfusion injury, and is a major cause of tissuedamage after loss of blood flow {Vedder et al., PNAS 87, 2643-2646(1990)}. TNFα also alters the properties of endothelial cells and hasvarious pro-coagulant activities, such as producing an increase intissue factor pro-coagulant activity, suppression of the anticoagulantprotein C pathway, and down-regulating the expression of thrombomodulin{Sherry et al., J Cell Biol. 107, 1269-1277 (1988)}. TNFα haspro-inflamnmatory activities which together with its early production(during the initial stage of an inflammatory event) make it a likelymediator of tissue injury in several important disorders including butnot limited to, myocardial infarction, stroke and circulatory shock. Ofspecific importance may be TNFα-induced expression of adhesionmolecules, such as intercellular adhesion molecule (ICAM) or endothelialleukocyte adhesion molecule (ELAM) on endothelial cells {Munro et al.,Am. J Path. 135(1), 121-132 (1989)}.

Moreover, it now is known that TNFα is a potent activator of retrovirusreplication including activation of HIV-1. {Duh et al., Proc. Nat. Acad.Sci. 86, 5974-5978 (1989); Poll et al., Proc. Nat. Acad. Sci. 87,782-785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et al., JImmunol. 142, 431-438 (1989); Poll et al., AIDS Res. Hum. Retrovirus,191-197 (1992)}. AIDS results from the infection of T lymphocytes withHuman Immunodeficiency Virus (HIV). At least three types or strains ofHIV have been identified, ie., HIV-1, HIV-2 and HIV-3. As a consequenceof HIV infection, T-cell mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HV entry into the T lymphocyte requires T lymphocyteactivation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytesafter T cell activation and such virus protein expression and/orreplication is mediated or maintained by such T cell activation. Once anactivated T lymphocyte is infected with HIV, the T lymphocyte mustcontinue to be maintained in an activated state to permit HIV geneexpression and/or HIV replication. Cytokines, specifically TNFα, areimplicated in activated T-cell mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with cytokine activity such as byprevention or inhibition of cytokine production, notably TNFα, in anHIV-infected individual assists in limiting the maintenance of Tlymphocyte caused by HIV infection.

Monocytes, macrophages, and related cells, such as kupffer and glialcells, also have been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells. {Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, 57 (1989)}. Cytokines, such as TNFα, have beenshown to activate HIV replication in monocytes and/or macrophages {Poliet al. Proc. Natl. Acad. Sci., 87, 782-784 (1990)}, therefore,prevention or inhibition of cytokine production or activity aids inlimiting HIV progression for T cells. Additional studies have identifiedTNFα as a common factor in the activation of HIV in vitro and hasprovided a clear mechanism of action via a nuclear regulatory proteinfound in the cytoplasm of cells (Osborn, et al., PNAS 86 2336-2340).This evidence suggests that a reduction of TNFα synthesis may have anantiviral effect in HIV infections, by reducing the transcription andthus virus production.

AIDS viral replication of latent HIV in T cell and macrophage lines canbe induced by TNFα {Folks et al., PNAS 86, 2365-2368 (1989)}. Amolecular mechanism for the virus inducing activity is suggested byTNFα's ability to activate a gene regulatory protein (NFκB) found in thecytoplasm of cells, which promotes HIV replication through binding to aviral regulatory gene sequence (LTR) {Osborn et al., PNAS 86, 2336-2340(1989)}. TNFα in AIDS associated cachexia is suggested by elevated serumTNFα and high levels of spontaneous TNFα production in peripheral bloodmonocytes from patients {Wright et al. J Immunol. 141(1), 99-104(1988)}. TNFα has been implicated in various roles with other viralinfections, such as the cytomegalia virus (CMV), influenza virus,adenovirus, and the herpes family of viruses for similar reasons asthose noted.

Reducing or inhibiting the production or action of TNFα, therefore,provides a potent therapeutic strategy for alleviation of manyinflammatory, infectious, immunological or malignant conditions. Theseinclude but are not restricted to septic shock, sepsis, endotoxic shock,hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury,malaria, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic disease, cachexia, graft rejection, cancer,autoimmune disease, opportunistic infections in AIDS, rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, other arthriticconditions, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythrematosis, ENL in leprosy, radiation damage, andhyperoxic alveolar injury. Efforts directed to the suppression of theeffects of TNFα have ranged from the utilization of steroids such asdexamethasone and prednisolone to the use of both polyclonal andmonoclonal antibodies {Beutler etal., Science 234, 470-474 (1985); WO92/11383}.

The nuclear factor κB (NFκB) is a pleiotropic transcriptional activator(Lenardo, et al. Cell 1989, 58, 227-29). NFκB has been implicated as atranscriptional activator in a variety of disease and inflammatorystates and is thought to regulate cytokine levels including but notlimited to TNFα and also to be an activator of HIV transcription(Dbaibo, et al. J Biol. Chem. 1993, 17762-66; Duh et al. Proc. Natl.Acad. Sci. 1989, 86, 5974-78; Bachelerie et al. Nature 1991, 350,709-12; Boswas et al. J. Acquired Immune Deficiency Syndrome 1993, 6,778-786; Suzuki et al. Biochem. And Biophys. Res. Comm. 1993, 193,277-83; Suzuki et al. Biochem. And Biophys. Res Comm. 1992, 189,1709-15; Suzuki et al. Biochem. Mol. Bio. Int. 1993, 31(4), 693-700;Shakhov et al. Proc. Natl. Acad. Sci. USA 1990, 171, 35-47; and Staal etal. Proc. Natl. Acad. Sci. USA 1990, 87, 9943-47). Thus, inhibition ofNFκB binding can regulate transcription of cytokine gene(s) and throughthis modulation and other mechanisms be useful in the inhibition of amultitude of disease states. The compounds described herein can inhibitthe action of NFκB in the nucleus and thus are useful in the treatmentof a variety of diseases including but not limited to rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, other arthriticconditions, septic shock, septis, endotoxic shock, graft versus hostdisease, wasting, Crohn's disease, ulcerative colitis, multiplesclerosis, systemic lupus erythrematosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in ADS. TNFα and NFκB levels are influenced bya reciprocal feedback loop. As noted above, the compounds of the presentinvention affect the levels of both TNFα and NFκB.

Many cellular functions are mediated by levels of adenosine 3',5'-cyclicmonophosphate (cAMP). Such cellular functions can contribute toinflammatory conditions and diseases including asthma, inflammation, andother conditions (Lowe and Cheng, Drugs of the Future, 17(9), 799-807,1992). It has been shown that the elevation of cAMP in inflammatoryleukocytes inhibits their activation and the subsequent release ofinflammatory mediators, including TNFα and NFκB. Increased levels ofcAMP also leads to the relaxation of airway smooth muscle. The primarycellular mechanism for the inactivation of cAMP is the breakdown of cAMPby a family of isoenzymes referred to as cyclic nucleotidephosphodiesterases (PDE), of which seven are known. It is recognized,for example, that the inhibition of PDE type IV is particularlyeffective in both the inhibition of inflammatory mediator release andthe relaxation of airway smooth muscle. Thus, compounds which inhibitPDE IV exhibit the desirable inhibition of inflammation and relaxationof airway smooth muscle with a minimum of unwanted side effects, such ascardiovascular or anti-platelet effects. It is now known that inhibitionof TNFα production can be a consequence of inhibition of PDE IV. L. J.Lombardo, Current Pharnaceutical design, 1, 255-268 (1995).

DETAILED DESCRIPTION

The present invention is based on the discovery that a class ofnon-polypeptide amides more fully described herein appear to inhibit theaction of TNFα and to elevate cAMP levels.

A first aspect of the present invention pertains to compounds of theformula: ##STR1## in which Z is: ##STR2## in which: R1 is the divalentresidue of (i) 3,4-pyridine, (ii) pyrrolidine, (iii) imidizole, (iv)naphthalene, (v) thiophene, or (vi) a straight or branched alkane of 2to 6 carbon atoms, unsubstituted or substituted with phenyl or phenylsubstituted with nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamyl, acetoxy, carboxy, hydroxy,amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, orhalo, wherein the divalent bonds of said residue are on vicinal ringcarbon atoms;

R2 is --CO-- or --SO2--;

R³ is (i) phenyl substituted with 1 to 3 substituents each selectedindependently from nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, or halo, (ii) pyridyl, (iii) pyrrolyl, (iv) imidazolyl, (v)naphthyl, (vi) thienyl, (vii) quinolyl, (viii) furyl, or (ix) indolyl;

R⁴ is alanyl, arginyl, glycyl, phenylglycyl, histidyl, leucyl,isoleucyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoseryl,threonyl, thyronyl, tyrosyl, valyl, benzimidol-2-yl, benzoxazol-2-yl,phenylsulfonyl, methylphenylsulfonyl, or phenylcarbamoyl; and

n has a value of 1, 2, or 3.

More particularly, a first preferred subclass pertains to compounds ofthe formula: ##STR3## in which R¹ is the divalent residue of (i)3,4-pyridine, (ii) pyrrolidine, (iii) imidizole, (iv) naphthalene, (v)thiophene, or (vi) a straight or branched alkane of 2 to 6 carbon atoms,unsubstituted or substituted with phenyl or phenyl substituted withnitro, cyano, trifluoromethyl carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, wherein thedivalent bonds of said residue are on vicinal ring carbon atoms; R² is--CO-- or --SO₂ --; and n has a value of 1, 2, or 3.

Preferred compounds of Formula IA include those in which R¹ is adivalent residue of pyridine, naphthalene or imidazole, R² is --CO--,and n is 2.

A second preferred subclass pertains to compounds of the formula:##STR4## in which R³ is (i) phenyl substituted with nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo, (ii) pyridyl, (iii)pyrrolyl, (iv) imidazolyl, (v) naphthyl, (vi) thienyl, (vii) quinolyl,(viii) fliryl, or (ix) indolyl; and

n has a value of 1, 2, or 3.

Preferred compounds of Formula IB are those wherein R³ istrifluoromethylphenyl, cyanophenyl, methoxyphenyl, fluorophenyl, orfuryl, and n is 2.

A third preferred subclass pertains to compounds of the formula:##STR5## in which R⁴ is alanyl, arginyl, glycyl, phenylglycyl, histidyl,leucyl, isoleucyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoseryl,threonyl, thyronyl, tyrosyl, valyl, benzimidol-2-yl, benzoxazol-2-yl,phenylsulfonyl, methylphenylsulfonyl, or phenylcarbamoyl, and n has avalue of 1, 2, or 3.

Preferred compounds of Formula IC are those wherein R⁴ is phenylsulfonylor 2-amino-3-phenylpropanoyl and n is 2.

A second aspect of the present invention pertains to compounds of theformula: ##STR6## in which R⁵ is (i) o-phenylene, unsubstituted orsubstituted with 1 to 4 substituents each selected independently fromnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino,dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to10 carbon atoms, or halo, or (ii) the divalent residue of pyridine,pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalentbonds are on vicinal ring carbon atoms;

R⁶ is --CO--, --CH₂ --, or --SO₂ --;

R⁷ is (i) hydrogen if R⁶ is --SO₂ --, (ii) straight, branched, or cyclicalkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl or phenylsubstituted with one or more substituents each selected independently ofthe other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylof 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (v)alkyl of 1 to 10 carbon atoms, (vi) benzyl unsubstituted or substitutedwith 1 to 3 substituents selected from the group consisting of nitro,cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo, (vii) naphthyl, (viii)benzyloxy, or (ix) imidazol-4-ylmethyl;

R¹² is --OH, alkoxy of 1 to 12 carbon atoms, or ##STR7## n has a valueof 0, 1, 2, or 3; R8' is hydrogen or alkyl of 1 to 10 carbon atoms; and

R⁹ ' is hydrogen, alkyl of 1 to 10 carbon atoms, --COR¹⁰, or --SO₂ R¹⁰in which R¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

A first preferred subclass of Formula II pertains to compounds of theformula ##STR8## in which R⁵ is (i) o-phenylene, unsubstituted orsubstituted with 1 to 4 substituents each selected independently fromnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino,dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to10 carbon atoms, or halo, or (ii) the divalent residue of pyridine,pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalentbonds are on vicinal ring carbon atoms;

R6 is --CO--, --CH2--, or --SO2--;

R⁷ is (i) hydrogen if R⁶ is --SO₂ --, (ii) straight, branched, or cyclicalkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl or phenylsubstituted with one or more substituents each selected independently ofthe other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, aikylof 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (v)alkyl of 1 to 10 carbon atoms, (vi) benzyl unsubstituted or substitutedwith 1 to 3 substituents selected from the group consisting of nitro,cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo, (vii) naphthyl, (viii)benzyloxy, or (ix) imidazol-4-ylmethyl;

n has a value of 0, 1, 2, or 3; R⁸ is hydrogen or alkyl of 1 to 10carbon atoms; and R⁹ is hydrogen, alkyl of 1 to 10 carbon atoms,--COR¹⁰, or --SO₂ R¹⁰ in which R¹⁰ is hydrogen, alkyl of 1 to 10 carbonatoms, or phenyl.

Preferred compounds of Formula IIA are those in which R⁵ is o-phenylene,R⁶ is --CO--; R⁷ is phenyl, substituted phenyl or pyridyl; n is 0 or 1,and each of R⁸ and R⁹ is hydrogen.

A second preferred subclass of Formula II pertains to compounds of theformula: ##STR9## in which R⁵ is (i) o-phenylene, unsubstituted orsubstituted with 1 to 4 substituents each selected independently fromnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino,dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or (ii) thedivalent residue of pyridine, pyrrolidine, imidizole, naphthalene, orthiophene, wherein the divalent bonds are on vicinal ring carbon atoms;

R⁶ is --CO--, --CH₂ --, or --SO₂ --;

R⁷ is (i) hydrogen if R⁶ is --SO₂ --, (ii) straight, branched, or cyclicalkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl or phenylsubstituted with one or more substituents each selected independently ofthe other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylof 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (v)alkyl of 1 to 10 carbon atoms, (vi) benzyl unsubstituted or substitutedwith 1 to 3 substituents selected from the group consisting of nitro,cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo, (vii) naphthyl, (viii)benzyloxy, or (ix) imidazol-4-ylmethyl; and

n has a value of 0, 1, 2, or 3.

Preferred compounds of Formula IIB are those in which R⁵ is o-phenylene,R⁶ is --CO--; R⁷ is phenyl, substituted phenyl or pyridyl; and n is 0 or1.

A third preferred subclass of Formula II pertains to compounds of theformula: ##STR10## in which R⁵ is (i) o-phenylene, unsubstituted orsubstituted with 1 to 4 substituents each selected independently fromnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino,dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or (ii) thedivalent residue of pyridine, pyrrolidine, imidizole, naphthalene, orthiophene, wherein the divalent bonds are on vicinal ring carbon atoms;

R⁶ is --CO--, --CH₂ --, or --SO₂ --;

R⁷ is (i) hydrogen if R⁶ is --SO₂ --, (ii) straight, branched, or cyclicalkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl or phenylsubstituted with one or more substituents each selected independently ofthe other from nitro, cyano, trifluoromethyl, carbethoxy, .carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylof 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (v)alkyl of 1 to 10 carbon atoms, (vi) benzyl unsubstituted or substitutedwith 1 to 3 substituents selected from the group consisting of nitro,cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo, (vii) naphthyl, (viii)benzyloxy, or (ix) imidazol-4-ylmethyl;

R12 is --OH or alkoxy of 1 to 12 carbon atoms; and

n has a value of 0, 1, 2, or 3.

Preferred compounds of Formula IIC are those in which R⁵ is o-phenylene,particularly aminophenylene, R⁶ is --CO--; R⁷ is phenyl, substitutedphenyl, particularly alkoxyphenyl and dialkoxyphenyl, or pyridyl; and nis 0 or 1.

The present invention also pertains to the physiologically acceptablenon-toxic acid addition salts of the compounds of Formula I. Such saltsinclude those derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lacticacid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid,aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthicacid, and the like.

Typical compounds of this invention include2-(2,6-dioxo-3-piperidinyl)-4-azaisoindoline-1,3-dione;2-(2,6-dioxo-3-piperidinyl)-benzo e!isoindoline-1,3-dione;5-(2,6-dioxo-3-piperidinyl)-pyrrolo 3,4-d!imidazole-4,6-dione;3-(trifluoromethylphenylcarboxamido)piperidine-2,6-dione;3-(cyanophenylcarboxamido)piperidine-2,6-dione;3-(methoxyphenylcarboxamido)-piperidine-2,6-dione;3-(3-pyridylcarboxamido)piperidine-2,6-dione;3-(2-furylcarboxamido)piperidine-2,6-dione;3-phenylsulfonamidopiperidine-2,6-dione;3-(2-amino-3-phenylpropanamido)-piperidine-2,6-dione;α-phthalimidophenylacetamide; 3-phthalimido-3-phenylpropionamide;2-phthalimido-3-phenylpropionamide;2-phthalimido-3-(4-hydroxyphenyl)propionamide;3-phthalimido-3-phenylpropionic acid; α-phthalimido4-hydroxyphenylaceticacid; α-phthalimidophenylacetic acid; α-phthalimido-4-fluorophenylaceticacid; α-phthalimido-2-fluorophenylacetic acid;α-phthalimido-4-fluorophenyl)acetamide; 2-phthalimido-3-phenylpropionicacid; 2-phthalimido-4-methylpentanoic acid;3-phenylcarboxamidopiperidine-2,6-dione; α-phthalimidoacetamide;3-phthalimidopropionamide; 3-phthalimidoimidazoline-2,5-dione;3-phenylcarboxamidopropionamide; 2-phthalimido-3-carbamoylpropionicacid; 2-(1,3-dioxo-4-azaisoindolin-2-yl)-3-carbamoylpropionic acid;3-(1,3-dioxo-4-azaisoindolin-2-yl)piperidine-2,6-dione;1,3-dioxo-4-azaisoindolin-2-ylacetamide;3-phthalimido-3-carbamoylpropionic acid; 4-phthalimidobutyramide;4-phthalimidobutyric acid; methyl3-phthalimido-3-(4-methoxyphenyl)propionate; ethyl3-phthalimido-3-(4-methoxyphenyl)propionate; methyl;3-phthalimido-3-phenylpropionate; and propyl3-phthalimido-3-(4-methoxyphenyl)propionate;α-(1-oxoisoindolin-2-yl)phenylacetic acid;α-(1-oxoisoindolin-2-yl)phenylacetamide;3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid;3-phenyl-2-(1-oxoisoindolin-2-yl)propionamide;3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid;3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide;3-(4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid;3-(4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide,3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid;3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide;3-(3,4-diethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid;3-(3,4-diethoxyphenyl)-3-phthalimidopropionamide;3-phthalimido-3-(4-propoxyphenyl)propionic acid;3-phthalimido-3-(4-propoxyphenyl)propionamnide; ethyl3-amino-3-(3-pyridyl)propionate hydrochloride; ethyl3-phthalimido-3-(3-pyridyl)propionate;3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid;3-phthalimido-3-(3,4-dimethoxyphenyl)propionamide;3-phthalimido-3-(3-ethoxy-4-methoxyphenyl)propionamide; ethyl3-amino-3-(3,4-dimethoxyphenyl)propionate; ethyl3-phthalimido-3-(3,4-dimethoxyphenyl)propionate; N-amyl3-phthalimido-3-(3,4-dimethoxyphenyl)propionamide; N-benzyl3-phthalimido-3-(3,4-dimethoxyphenyl)propionamide; N-ethyl3-phthalimido-3-(3,4-dimethoxyphenyl)propionamide;3-phthalimido-3-(4-ethoxyphenyl)propionic acid;3-phthalimnido-3-(4-ethoxyphenyl)propionamide;3-(cis-hexahydrophthalimido)-3-phenylpropionic acid;3-(cis-hexahydrophthalimido)-3-phenylpropionamide;3-(4-methylphthalimido)-3-phenylpropionic acid;3-(cis-5-norbonene-endo-2,3-dicarboxylic imide)-3-phenylpropionic acid;3-(2,3,4,5-tetrachlorophthalimido)-3-(4-methoxyphenyl)propionic acid;3-(2,3,4,5-tetrafluorophthalimido)-3-(4-methoxyphenyl)propionic acid;3-(1-oxo-4,5,6,7-tetrafluoroisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionicacid;3-(1-oxo-4,5,6,7-tetrafluoroisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionamide;methyl3-(1-oxo-4,5,6,7-tetrafluoroisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;3-(1-oxo-4,5,6,7-tetrafluoroisoindolin2-yl)-3-(4-methoxyphenyl)propionicacid;3-(1-oxo-4,5,6,7-tetrafluoroisoindolin-2-yl)-3-(4-methoxyphenyl)propionamide;methyl3-(1-oxo-4,5,6,7-tetrafluoroisoindolin-2-yl)-3-(4-methoxyphenyl)propionate;3-(1-oxo-4-aminoisoindolin-2-yl)-3-(4-methoxyphenyl)propionic acid;3-(1-oxo-4-amninoisoindolin-2-yl)-3-(4-methoxyphenyl)propionamide;methyl 3-(1-oxo-4-aminoisoindolin-2-yl)-3-(4-methoxyphenyl)propionate;3-(4-nitrophthalimido)-3-(4-methoxyphenyl)propionic acid;3-phthalimido-3-(2-naphthyl)propionic acid;3-phthalimido-3-(2-naphthyl)propionamide; methyl3-(1,3-dioxo-5-azaisoindol-2-yl)-3-(3,4-dimethoxyphenyl)-propionate;3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionic acid;3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionamide;3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionic acid;3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionamide;α-(3,4,5,6-tetrachlorophthalimidio)phenylacetic acid;α-(4,5-dichlorophthalimido)phenylacetic acid; α-(3-nitrophthalimido)phenylacetic acid; 3-(4-methoxyphenyl)-3-(3-nitrophthalimido)propionicacid; 3-(4,5-dichlorophthalimido)-3-(4-methoxyphenyl)propionic acid;3-pyridinemethyl 3-phthalimido-3-(3,4-dimethoxyphenyl)propionate;N-3-methylpyridyl 3-phthalimido-3-(3,4-dimethoxyphenyl)propionamide;3-phthalimido-3-(3,4-dichlorophenyl)propionamide; methyl3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride; methyl3-phthalimido-3-(3,4-dimethoxyphenyl)propionate; methyl(S)-N-benzyl-N-(R)-α-methylbenzyl-3-(3,4-dimethoxyphenyl)propionate;methyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride;methyl (S)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionate; methyl(R)-3-(N-benzyl-N-(S)-α-methylbenzylamino)-3-(3,4-dimethoxyphenyl)propionate;methyl (R)-3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride;3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionic acid,3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionic acid,3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionamide,3-(1-oxoisoindolin-2-yl)-3-(3-butoxy4-methoxyphenyl)propionamide, methyl3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionate, methyl3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate, andmethyl (3R)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionate.

The term alkyl as used herein denotes a univalent saturated branched orstraight hydrocarbon chain. Unless otherwise stated, such chains cancontain from 1 to 10 carbon atoms. Representative of such alkyl groupsare methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl,heptyl, octyl, nonyl, decyl, and the like. When qualified by "lower",the alkyl group will contain from 1 to 6 carbon atoms. The same carboncontent applies to the parent term "alkane" and to derivative terms suchas "alkoxy".

The compounds can be used, under the supervision of qualifiedprofessionals, to reduce the undesirable effects of TNFα. The compoundscan be administered orally, rectally, or parenterally, alone or incombination with other therapeutic agents including antibiotics,steroids, etc., to a mammal in need of treatment. Oral dosage formsinclude tablets, capsules, dragees, and similar shaped, compressedpharmaceutical forms. Isotonic saline solutions containing 20-100 mg/mLcan be used for parenteral administration which includes intramuscular,intrathecal, intravenous and intra-arterial routes of administration.Rectal administration can be effected through the use of suppositoriesformulated from conventional carriers such as cocoa butter.

Dosage regimens must be titrated to the particular indication, the age,weight, and general physical condition of the patient, and the responsedesired but generally doses will be from about 10 to about 500 mg/day asneeded in single or multiple daily administration. In general, aninitial treatment regimen can be copied from that known to be effectivein interfering with TNFα activity for other TNFα mediated disease statesby the compounds of the present invention. Treated individuals will beregularly checked for T cell numbers and T4/T8 ratios and/or measures ofviremia such as levels of reverse transcriptase or viral proteins,and/or for progression of cytokine-mediated disease associated problemssuch as cachexia or muscle degeneration. If no effect is observedfollowing the initial treatment regimen, then the amount of compoundadministered can be increased by, for example, fifty percent a week.

The compounds of the present invention also can be used topically in thetreatment or prophylaxis of topical disease states mediated orexacerbated by excessive TNFα production, respectively, such as viralinfections, such as those caused by the herpes viruses, or viralconjunctivitis, etc.

The compounds also can be used in the veterinary treatment of mammalsother than humans in need of prevention or inhibition of TNFαproduction. TNFα mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedabove, but in particular viral infections. Examples include felineimmunodeficiency virus, equine infectious anaemia virus, caprinearthritis virus, visna virus, and maedi virus, as well as otherlentiviruses.

Certain of these compounds possess centers of chirality and can exist asoptical isomers. Both the racemates of these isomers and the individualisomers themselves, as well as diastereomers when there are two chiralcenters, are within the scope of the present invention. The racematescan be used as such or can be separated into their individual isomersmechanically as by chromatography using a chiral absorbant.Alternatively, the individual isomers can be prepared in chiral form orseparated chemically from a mixture by forming salts with a chiral acid,such as the individual enantiomers of 10-camphorsulfonic acid, camphoricacid, α-bromocamphoric acid, methoxyacetic acid, tartaric acid,diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, andthe like, and then freeing one or both of the resolved bases, optionallyrepeating the process, so as obtain either or both substantially free ofthe other; i.e., in a form having an optical purity of >95%.

The compounds can be prepared using methods which are known in generalfor the preparation of amides. An N-alkoxycarbonylimide and an aminethus are allowed to react in the presence of a base such as sodiumcarbonate or sodium bicarbonate substantially as described by Shealy etal., Chem. & Ind., (1965) 1030-1031) and Shealy et al., J. Pharm. Sci.57, 757-764 (1968) to yield the N-substituted amide. Alternatively, acyclic acid anhydride can be reacted with an appropriate amine to forman amide. Formation of a cyclic amide also can be accomplished byrefluxing a solution of an appropriately substituted dicarboxylic acidmonoamide in anhydrous tetrahydrofuran with N,N'-carbonyldiimidazole. Incontrast to prior art methods which produced a yield of less than 50%,this reaction produces yields in excess of 60%, in some cases greaterthan 90%.

Prevention or inhibition of production of TNFα by these compounds can beconveniently assayed using anti-TNFα antibodies. For example, plates(Nunc Immunoplates, Roskilde, DK) are treated with 5 μg/mL of purifiedrabbit anti-TNFα antibodies at 4° C. for 12 to 14 hours. The plates thenare blocked for 2 hours at 25° C. with PBS/0.05% Tween containing 5mg/mL BSA. After washing, 100 μL of unknowns as well as controls areapplied and the plates incubated at 4° C. for 12 to 14 hours. The platesare washed and assayed with a conjugate of peroxidase (horseradish) andmouse anti-TNFα monoclonal antibodies, and the color developed witho-phenylenediamine in phosphate-citrate buffer containing 0.012%hydrogen peroxide and read at 492 nm.

The following examples will serve to further typify the nature of thisinvention but should not be construed as a limitation in the scopethereof, which scope is defined solely by the appended claims.

EXAMPLE 1

A stirred suspension of (S)-glutamine (14.6 g, 100 mmol) and2,3-pyridinedicarboxylic anhydride (14.9 g, 100 mmol) in 100 mL ofacetic acid is heated and refluxed for 1 hour. The reaction solution iscooled to form a solid. The solid is removed by filtration and washedwith acetic acid to yield 7.11 g (26%) of2-(1,3-dioxo-4-azaisoindolin-2-yl)glutaramic acid. The product can befurther purified by slurring in 700 mL of refluxing ethanol, cooling,filtering, and drying to produce a white powder with a melting point of222°-226° C.; ¹ H NMR (DMSO-d₆) δ 13.25 (br s, 1 H, COOH), 9.04 (dd, 1H, J=1.2, 4.9 Hz, pyr), 8.37 (dd, 1 H, J=1.2, 7.8 Hz, pyr), 7.85 (dd, 1H, J=4.9, 7.8 Hz, pyr), 7.20 (s, 1₋₋ H, CONH₂), 6.73 (s, 1 H, CONH₂),4.83 (dd, 1 H, J=10.2, 4.8 Hz, CHN), 2.55-1.90 (m, 4 H, CH₂ CH₂); ¹³ CNMR (DMSO-d₆) δ 1173.22, 170.21, 165.8, 165.7, 155.4, 150.9, 131.7,128.3, 126.9, 51.5, 31.4, 24.0.

Utilization of asparagine in place of glutamine produces2-(1,3-dioxo-4-azaisoindolin-2-yl)-malonamic acid.

By substituting equivalent amounts of 2,3-naphthalenedicarboxylicanhydride and 4,5-imidazoledicarboxylic anhydride for2,3-pyridinedicarboxylic anhydride in the foregoing procedure, there arerespectively obtained 2-(1,3-dioxobenzo e!isoindolin-2-yl)glutaramicacid and 2-(4,6-dioxopyrrolo 3,4-d!imidazol-5-yl)glutaramic acid.

EXAMPLE 2

A stirred suspension of 1.39 g, 5.01 mmol, of2-(1,3-dioxo-4-azaisoindolin-2-yl)glutaramic acid (see Example 1),N,N'-carbonyldiimidazole (0.890 g, 5.49 mmoL) andN,N-dimethylaminopyridine (0.005 g, 0.04 mmoL) in 20 mL oftetrahydrofuran is refluxed for 15 hours. The reaction slurry is cooledand the solid removed by filtration and washed with minimaltetrahydrofuran. 2-(2,6-Dioxo-3-piperidinyl)-4-azaisoindoline-1,3-dione(0.859 g, 66%) is recovered as a white powder. ¹ H NMR (DMSO-d₆) δ 11.18(s, 1 H, NHCO), 9.04 (d, 1 H, J=5.0 Hz, pyr), 8.39 (d, 1 H, J=7.7 Hz,pyr), 7.86 (dd, 1 H, J=5.0, 7.7 Hz, pyr), 5.25 (dd, 1 H, J=15.3, 13 Hz,1 H, CHCO), 3.05-2.75 (m, 1 H, CH₂ CO), 2.75 (m, 2 H, CH₂ CO, CH₂),2.20-2.00 (m, 1 H, CH₂ CO, CH₂); ¹³ C NMR (DMSO-d₆) δ 172.6, 169.6,165.4, 155.3, 150.8, 131.7, 128.2, 126.9, 49.0, 30.8, 21.8. Anal. Calcdfor C₁₂ H₉ N₃ O₄. Theory 55.60, 3.50, 16.21. Found 55.50, 3.53, 16.11.

Substitution of 2-(1,3-dioxo-4-azaisoindolin-2-yl)malonamic acid in theforegoing procedure yields2-(2,5-dioxo-3-pyrrolidinyl)-4-azaisoindoline-1,3-dione.

By substituting equivalent amounts of 2-(1,3-dioxobenzoe!isoindolin-2-yl)glutaramic acid and 2-(4,6-dioxopyrrolo3,4-d!imidazol-5-yl)glutaramic acid in the foregoing procedure, thereare respectively obtained 2-(2,6-dioxo-3-piperidinyl)benzoe!isoindoline-1,3-dione and 5-(2,6-dioxo-3-piperidinyl)-pyrrolo3,4-d!imidazole4,6-dione.

EXAMPLE 3

A solution of L-glutamine (2.92 g, 20.0 mmoL) and sodium hydroxide (20mmoL) in water is added to a stirred solution of phenylisocyanate (2.4g, 2.2 mL, 20 mmoL) in acetonitrile (40 mL). The reaction mixture isstirred for 45 hours and is partially concentrated to removeacetonitrile. The reaction mixture is washed with ethyl acetate (2×25 mLeach). The pH of the reaction mixture is adjusted to 1-2 with 4Nhydrochloric acid. The slurry of the reaction mixture is filtered andthe solid washed and dried to yield 4.70 g ofN-phenyl-N'-(4-carboxybutyramide)urea (89%) as a white powder.

By substituting 4-trifluoromethylphenylisocyanate,3-cyanophenylisocyanate, 2-methoxyphenylisocyanate, fur-2-ylisocyanate,and pyrid-3-ylisocyanate for phenylisocyanate in the foregoingprocedure, there are respectively obtainedN-(4-trifluoromethylphenyl)-N'-(4-carboxybutyramide)urea,N-(3-cyanophenyl)-N'-(4-carboxybutyramide)urea,N-(2-methoxyphenyl)-N'-(4-carboxybutyramide)urea,N-(fur-2-yl)-N'-(4-carboxybutyramide)urea, andN-(pyrid-3-yl)-N'-(4-carboxybutyrarnide)urea.

EXAMPLE 4

N-Phenyl-N'-(4-carboxybutyramide)urea (2.00 g, 7.54 mmoL) is mixed withcarbonyldiimidazole (1.24 g, 7.95 mmoL) in tetrahydrofuran (30 mL) isheated and refluxed for 16 hours. The reaction mixture is concentratedand the residue slurried in water (25 mL). The resulting slurry isfiltered and the solid is washed with water and air dried to yield 0.63g of 3-phenylcarboxamidopiperidine-2,6-dione which can be alternativelynamed as N-phenyl-N'-(2-glutarimide)urea as a white flocculent powder.After being allowed to stand, the filtrate is refiltered to yield 0.70 gof additional material. ¹ H NMR (DMSO-d₆) δ 8.51 (s, 1H, CONHCO),7.6-7.2 (m, 6 H, Ar, ArNH), 6.83 (s, 1 H, NHCH), 4.26 (t, 1₋₋ H, CHCO),2.4-1.8 (m, 4 H, CH₂ CH₂); ¹³ C NMR (DMSO-d₆) δ 173.2, 155.6, 132.2,128.7, 127.7, 126.7, 55.7, 29.8, 27.2. Anal. Calcd for C₁₂ H₁₃ N₃ O₃.Theoretical: C, 58.29; H, 5.29; N, 16.99. Found: C, 58.12; H, 5.17; N,17.02.

By substitutingN-(4-trifluoromethylphenyl)-N'-(4-carboxybutyramide)urea,N-(3-cyanophenyl)-N'-(4-carboxybutyramide)urea,N-(2-methoxyphenyl)-N'-(4-carboxybutyramide)urea,N-(fur-2-yl)-N'-(4-carboxybutyramide)urea, andN-(pyrid-3-yl)-N'-(4-carboxybutyramide)urea forN-phenyl-N'-(4-carboxybutyramide)urea in the foregoing procedure, thereare respectively obtained3-(4-trifluoromethylphenylcarboxamido)piperidine2,6-dione,3-(3-cyanophenylcarboxamido)piperidine-2,6-dione,3-(2-methoxyphenylcarboxamido)piperidine-2,6-dione,3-(fur-2-ylcarboxamido)piperidine-2,6-dione, and3-(pyrid-3-ylcarboxantido)piperidine-2,6-dione.

EXAMPLE 5

To a stirred mixture of phenylglycine (3.0 g, 20 mmoL) and sodiumcarbonate (2.23 g, 21 mmoL) in 450 mL of water is addedN-carbethoxyphthalimide (4.38 g, 20 mmoL). After 45 minutes, thereaction slurry is filtered. The filtrate is stirred and the pH adjustedto 1-2 with 4N hydrochloric acid. After 1 hour, the resulting slurry isfiltered and the solid washed with water. The solid is dried in vacuo(60° C., <1 mm) to afford 2.88 g (51%) of α-phthalimidophenylaceticacid, which can be alternatively named as N-phthaloylphenylglycine, as awhite powder.

Use of β-phenyl-β-alanine, α-phenyl-β-alanine, histidine, and tyrosinein place of phenylglycine in the procedure of this example yieldsrespectively 3-phthalimido-3-phenylpropionic acid,3-phthalimido-2-phenylpropionic acid,2-phthalimido-3-imidazolylpropionic acid, and2-phthalimido-3-(4-hydroxyphenyl)propionic acid.

EXAMPLE 6

To a stirred mixture of α-phthalimidophenylacetic acid (2.50 g, 8.89mmoL) in tetrahydrofuran (50 mL) is added carbonyldiimidazole (1.50 g,9.25 mmoL) and a few crystals of 4-dimethylaminopyridine. The reactionis then heated to 50° C. for 45 minutes. After the reaction mixturecools to room temperature, 1 mL of concentrated ammonium hydroxide isadded via syringe. The reaction is stirred for 1 hour, then diluted with50 mL of water and partially concentrated to remove the majority of thetetrahydrofuran. The resulting slurry is filtered and the solid washedwith copious amounts of water. The solid is dried in vacuo (60° C., <1mm) to afford 1.9 g (76%) of α-phthalimidophenylacetamide, which may bealternatively named as N-phthaloylphenylglycinamide, as an off-whitepowder: mp 218°-220° C.; ¹ H NMR (DMSO-d₆) δ 9.00-7.75 (m, 4 H, Ar),7.61 (br s, 1 H, CONH₂), 7.55-7.20 (m, 6 H, Ar, CONH₂), 5.82 (s, 1 H,CHCO₂); ¹³ C NMR (DMSO-d₆) δ 168.2, 167.1, 135.6, 134.5, 131.4, 129.4,127.9, 127.7, 123.1, 56.3. Anal (C₁₆ H₁₂ N₂ O₃), C, H, N.

Use of 3-phthalimido-3-phenylpropionic acid,2-phthalimido-3-phenylpropionic acid,2-phthalimido-3-imidazolylpropionic acid, and2-phthalimido-3-(4-hydroxyphenyl)propionic acid in place ofα-phthalimidophenylacetic acid in the procedure of this example yieldsrespectively 3-phthalimido-3-phenylpropionamide,2-phthalimido-3-phenylpropionamide,2-phthalimido-3-imidazolylpropionamide, and2-phthalimido-3-(4-hydroxy)phenylpropionamide.

EXAMPLE 7

To a stirred mixture of β-alanine (4.45 g, 50.0 mmoL) and sodiumcarbonate (5.35 g, 50.5 mmoL) in 100 mL of water is addedN-carbethoxyphthalimide (10.95 g, 50.0 mmoL). After 1.5 hour, thereaction slurry is filtered. The filtrate is stirred and the pH adjustedto 1-2 with 4N hydrochloric acid. After 15 minutes, the resulting slurryis filtered and the solid washed with water. The solid is dried in vacuo(60° C., <1 mm) to afford 6.96 g (64%) of N-phthaloyl-β-alanine, whichcan be alternatively named as 3-phthalimidopropionic acid, as a whitepowder.

EXAMPLE 8

To a stirred solution of N-phthaloyl-β-alanine (2.19 g, 10.0 mmoL) intetrahydrofuran (25 mL) is added carbonyldiimidazole (1.62 g, 10.0 mmoL)and a few crystals of 4-N,N-dimethylaminopyridine followed by 15 mL oftetrahydrofuran. The reaction is then heated to 40°-45° C. for 1 hour.After the reaction mixture cools to room temperature, 1 mL ofconcentrated ammonium hydroxide is added via syringe. The reaction isstirred for 20 minutes and the resulting slurry filtered and the solidwashed with tetrahydrofuran. The solid is dried in vacuo (60° C, <1 mm)to afford 1.72 g (79%) of N-phthaloyl-β-alanine amide, which can bealternatively named as 3-phthalimidopropionamide, as a white powder: mp252°-253° C.; ¹ H NMR (DMSO-d₆) δ 8.00-7.70 (m, 4 H, Ar), 7.45 (br s, 1H, CONH₂), 6.89 (br s, 1 H, CONH₂), 3.78 (t, 2 H, J=7 Hz, CH₂ CO), 2.43(t, 2 H, CH₂); ¹³ C NMR (DMSO-d₆) δ 171.5, 167.6, 134.2, 131.6, 122.9,34.1, 33.5. Anal. Calcd for C₁₁ H₁₀ N₂ O₃. Theoretical: C, 60.55; H,4.62; N, 12.84. Found: C, 60.49; H, 4.59; N, 12.82.

EXAMPLE 9

To a stirred solution of glycinamide hydrochloride (2.20 g, 20.0 mmoL)and sodium carbonate (2.54 g, 24 mmoL) in 25 mL of water is addedN-carbethoxyphthalimide (4.38 g, 20.0 mmoL). The resulting suspension isstirred for 1.5 hour and then filtered to afford 3.22 g (79%) of thecrude product as a white powder. The crude product is slurried in 200 mLof refluxing ethanol. The resulting suspension after cooling to roomtemperature is filtered and the solid dried in vacuo (60° C., <1 mm) toafford 2.65 g (65%) of N-phthaloylglycinamide as a white powder: mp199°-201° C.; ¹ H NMR (DMSO-d₆) δ 8.00-7.8 (m, 4 H, Ar), 7.70 (br s, 1H, CONH₂), 7.26 (br s, 1 H, CONH₂), 4.16 (s, 2 H, CH₂); ¹³ C NMR(DMSO-d₆) δ 167.8, 167.5, 134.4, 131.7, 123.1, 39.9. Anal. Calcd for C₁₁H₁₀ N₂ O₃. Theoretical: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.49; H,4.59; N, 12.82.

EXAMPLE 10

To a stirred solution of L-glutamine (43.8 g, 300 mmoL) and sodiumcarbonate (33.4 g, 315 mmoL) in 750 mL of water is rapidly addedN-carbethoxyphthalimide 65.8 (97% pure, 67.8 g), 300 mmoL! as a solid.After 1 hour, the reaction mixture is filtered to remove unreactedN-carbethoxyphthalimide. The pH of the stirred filtrate is adjusted to3-4 with 4N hydrochloric acid. The mixture is then seeded withN-phthaloyl-L-glutamine and the pH adjusted to 1-2 with 4N hydrochloricacid. The resulting slurry is stirred for 1 hour. The slurry is filteredand the solid washed with copious amounts of water. The solid isair-dried and then dried in vacuo (60° C., <1 mm) overnight to afford49.07 g (59%) of N-phthaloyl-L-glutamine, which can be alternativelynamed as 2-phthalimidoglutaramic acid, as a white powder.

EXAMPLE 11

A stirred mixture of N-phthaloyl-L-glutamine (48.0 g, 174 mmoL),carbonyldiimidazole (30.43 g, 188 mmoL), and 4-dimethylaminopyridine(0.105 g, 0.861 mmoL) in anhydrous tetrahydrofuran (300 mL) is heated toreflux for 16 hours. The reaction slurry is filtered and the solidwashed with methylene chloride (200 mL). The solid is air-dried and thendried in vacuo (60° C., <1 mm) to afford 40.40 g (90%) of thalidomide asa white powder. ¹ HNMR (DMSO-d₆) δ 11.16 (s, 1 H, NH), 8.05-7.80 (br s,4 H, Ar), 5.18 (dd, 1 H, J=12, 5 Hz, CHCO), 3.05-2.85 (m, 1 H, CH₂ CO),2,70-2.45 (m, 2 H, CH₂ CH ₂), 2.15-2.00 (M, 1 H, CH₂). ¹³ C NMR(DMSO-d₆) δ 172.8, 169.8, 167.1, 134.9, 131.2, 123.4, 49.0, 30.9, 22.0.

EXAMPLE 12

By employing (R)-phenylglycine in the procedure of Example 5, there isobtained (R)-α-phthalimidophenylacetic acid, as a white powder: mp175°-177° C.; 1H NMR (DMSO-d₆, 250 M Hz) δ 12.50 (br s, 1H), 7.95-7.85(m, 4H), 7.55-7.28 (m, 5H), 6.04 (s, 1H); 13C NMR (DMSO-d₆) δ 168.9,166.9, 135.0, 134.9, 131.0, 129.1, 128.1, 127.9, 123.5, 56.1. Anal.Calculated for C₁₆ H₁₁ NO₄. Theoretical: C, 68.32; H, 3.94; N, 4.98.Found: C, 68.32; H, 3.85; N, 4.95.

Likewise from (S)-phenylglycine, there is obtained(S)-α-phthalimidophenylacetic acid as a white powder: mp 180°-184° C.;1H NMR (DMSO-d₆, 250 M Hz) δ 12.5 (br s, 1H), 7.95-7.85 (m, 4H),7.55-7.28 (m, 5H), 6.04 (s, 1H); 13C NMR (DMSO-d₆) δ 168.9, 166.9,135.0, 134.9, 130.9, 129.1, 128.1, 127.9, 123.5, 55.1. Anal. Calculatedfor C₁₆ H₁₁ NO₄. Theoretical: C, 68.32; H, 3.94; N, 4.98. Found: C,68.14; H, 3.87; N, 4.96.

EXAMPLE 13

To a stirred solution of N-phthaloylglycine (2.50 g, 8.89 mmol) intetrahydrofuran (50 mL) is added carbonyldiimidazole (1.50 g, 9.25 mmol)and a few crystals of 4-N,N-dimethylaminopyridine. The reaction is thenheated to 50° C. for 45 minutes. After the reaction mixture had cooledto room temperature, 1 mL of concentrated ammonium hydroxide is addedvia syringe. The reaction is stirred for 1 hour, then diluted with 50 mLof water and partially concentrated to remove the majority of thetetrahydrofuran. The resulting slurry was filtered and the solid washedwith copious amounts of water. The solid was dried in vacuo (60° C., <1mm) to afford 1.9 g (76%) of α-phthalimidophenylacetamide as anoff-white powder: mp 218°-220° C.; 1H NMR (DMSO-d₆) δ 9.00-7.75 (m, 4 H,Ar), 7.61 (br s, 1 H, CONH₂), 7.55-7.20 (m, 6 H, Ar, CONH₂), 5.82 (s, 1H, CHCO₂); 13C NMR (DMSO-d₆) δ 168.2, 167.1, 135.6, 134,5, 131.4, 129.4,127.9, 127.7, 123.1, 56.3.

EXAMPLE 14

By following the procedure of Example 8 but utilizing an equivalentamount of 4-aminobutyric acid, there is obtained a 67% yield of4-phthalimidobutyric acid as a white powder: mp 108°-111° C.; 1H NMR(DMSO-d₆) δ 12.10 (s, 1 H), 7.92-7.75 (m, 4 H, Ar), 3.62 (t, J=6.8 Hz, 2H), 2.29 (t, J=7.2 Hz, 2 H), 1.90-1.76 (m, 2 H); 13C NMR (DMSO-d₆) δ173.8, 167.9, 134.2, 131.6, 122.9, 36.8, 30.9, 23.3.

EXAMPLE 15

By following the procedure of Example 15 but utilizing an equivalentamount of 4-phthalimidobutyric acid, there is obtained4-phthalimdobutyramide as a white powder in a 23% yield: mp159.5°-161.5° C.; 1H NMR (DMSO-d₆) δ 8.0-7.7 (m, 4 H, Ar), 3.58 (t,J=6.9 Hz, 2 H), 2.09 (t, 2 H, 1.92-1.70 (m, 2 H; 13C NMR (DMSO-d₆) δ173.3, 167.9, 134.2, 131.6, 122.9, 37.1.32.3, 23.9.

EXAMPLE 16

By following the procedure of Example 19 but employingN-carbethoxyphthalimide and (S)-phenylalaninamide hydrochloride, thereis obtained (S)-2-phthalimido-3-phenylpropionamide which can berecrystallized from ethanol to afford white crystals: mp 211°-215° C.;1H NMR (DMSO-d₆) δ 7.92 (s, 5 H, Ph), 7.72, 7.33 (2 s, 2 H), 7.2-7.0 (m,4 H, Ar), 4.92 (dd, 1H, J=12,4.5 Hz), 3.52 (dd, 1 H, J=4.3, 13.9), 3.35(dd, 1 H, J=12, 13.9); 13C NMR (DMSO-d₆) δ 169.6, 167.4, 137.7, 134.3,131.2, 128.5, 128.1, 126.3, 122.9, 54.2, 33.7.

EXAMPLE 17

To a stirred solution of d,1-phenylalanine (4.17 g, 25.0 mmol) andsodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is addedN-carboethoxyphthallmde (5.65 g, 25.0 mmol). The resulting slurry isstirred for 1.5 hour and filtered. The pH of the filtrate is adjusted to1-2 with 4N hydrochloric acid with stirring. After 20 minutes, theslurry is refiltered and the solid washed with water. The solid is driedin vacuo (60° C., <1 mm) to afford 5.44 g (74%) of2-phthalimido-3-phenylpropionic acid as a white powder: mp 165°-169° C.;1H NMR (DMSO-d₆, 250 M Hz) δ 12.5(br s, 1H), 7.84(s, 4H), 7.23-7.06 (m,5H), 5.13 (dd, 1H, J=5.0), 3.26-3.05 (m, 2H); 13C NMR (250 MHz, DMSO-d₆)δ 170.0, 167.0, 137.2, 134.8, 130.6, 128.6, 128.2, 126.5, 123.3, 52.8,33.8. Anal. Calculated for C₁₇ H₁₃ NO₄. Theoretical: C, 69.15; H, 4.44;N, 4.74. Found: C, 69.07; H, 4.34; N, 4.78.

EXAMPLE 18

To a stirred solution of 2-phthalimido-3-phenylpropionic acid (2.95 g,10.0 mmol) in tetrahydrofuiran (25 mL) are added carbonyldiimridazole(1.62 g, 10.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine,followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred atroom temperature for 45 minutes and 1 mL of concentrated ammoniumhydroxide then is added. After 10 minutes, the reaction mixture isdiluted with 50 mL water and the resulting slurry is partiallyconcentrated to remove the tetrahydrofuran and filtered. The solid iswashed with water and dried in vacuo (60° C., <1 mm) to afford 2.46 g(84%) of 2-phthalimido-3-phenylpropionamide as a white powder: mp224°-226° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 7.79 (s, 4 H, Ar), 7.71 (br s,1 H, CONH2), 7.32 (br s, 1 H, CONH2), 7.20-7.02 (m, 5H, Ar), 5.06-4.98(m, 1H), 3.56-3.25 (m, 2H); 13C NMR (DMSO-d₆, 250 MHz) d: 169.6, 168.0,137.1, 134.3, 131.2, 129.5, 128.1, 126.3, 122.9, 54.2, 33.7. Anal.Calculated for C₁₇ H₁₄ N₂ O₃. Theoretical: C, 69.38; H, 4.79; N, 9.52.Found: C, 69.37; H, 4.73; N, 9.43.

EXAMPLE 19

To a stirred solution of 4-fluorophenylglycine (3.38 g, 20.0 mmol) andsodium carbonate in 450 mL of 2:1 water:acetonitrile is addedN-carbethoxyphthalimide (4.38 g, 20 mmol). After 1 hour, the reactionmixture is partially concentrated to remove the acetonitrile. Theresulting slurry is filtered and the pH of the stirred filtrate isadjusted to 1-2 with 4N hydrochloric acid and then stirred for anadditional 30 minutes and filtered. The solid is air-dried and thendried in vacuo (60° C., <1 mm) to afford 4.55 g (76%) ofα-phthalimido4-fluorophenylacetic acid as a white powder: mp 180°-183°C.; 1H NMR (DMSO-d₆, 250 MHz) δ 8.10-7.80 (m, 4 H), 7.65-7.45 (m, 4 H),7.3-7.10 (t, 2 H), 6.10 (s, 1 H); 13C NMR (DMSO-d₆, 250 MHz) δ 168.9,166.9, 163.6, 159.7, 135.0, 131.4, 131.3 (m), 130.9, 123.5, 115.0,114.7, 54.4. Anal. Calculated for C₁₆ H₁₀ NO₄ F. Theoretical: C, 64.22;H, 3.37; N, 4.68. Found: C, 64.13; H, 3.33; N, 4.63.

Similarly prepared from 2-fluorophenylglycine isα-phthalimido-2-fluorophenylacetic acid as a white solid: mp174.5°-180.5° C.; 1H NMR (DMSO-d₆) δ 13.8 (br s, 1 H), 7.65-7.15 (m,4H), 6.18 (s, 1 H); 13C NMR (DMSO-d₆) δ 168.1, 166.8, 162.1, 158.2,135.0, 130.9, 130.8, 130.5, 130.4, 124.1. 123.6, 121.8, 121.6, 115.3,114.9, 48.9. Anal. Calculated for C₁₆ H₁₀ NO₄ F. Theoretical: C, 64.22;H, 3.37; N, 4.68. Found: C, 63.93; H, 3.27; N, 4.68.

EXAMPLE 20

Similarly prepared according to the procedure of Example 18 fromα-phthalimido-4-fluorophenylacetic acid, carbonyldiimidazole,4-N,N-dimethylaminopyridine and concentrated ammonium hydroxide isα-phthalimido-4-fluorophenylacetamide which can be recrystallized fromtetrahydrofuran to afford 0.76 g (51%) of the product as white crystals:mp 180°-183° C.; 1H NMR (DMSO-d₆) δ 8.00-7.55 (m, 4 H), 7.64 (s, 1 H),7.60-7.40 (m, 3 H), 7.25-7.05 (m, 2 H), 5.83 (s, 1 H). Anal. Calculatedfor C₁₆ H₁₁ N₂ O₃ F. Theoretical: C, 64.43; H, 3.72; N, 9.39. Found: C,64.16; H, 3.62; N, 9.18.

Likewise from α-phthalimido-2-fluorophenylacetic acid there is obtainedα-phthalimido-2-fluorophenylacetamide as small white crystals: mp197°-201° C.; 1H NMR (DMSO-d₆) δ 8.05-7.75 (m, 5 H), 7.65-7.05 (m, 5 H),6.06 (s, 1 H), 13C NMR (DMSO-d₆) δ 167.4, 166.9, 162.2, 158.3, 134.6,131.3, 131.2, 131.1, 130.2, 130.0, 123.9, 123.8, 123.2, 122.4, 115.1,114.8, 49.9.

EXAMPLE 21

To a stirred solution of d,1-leucine (3.31 g, 25.0 mmol) and sodiumcarbonate (2.78 g, 26.25 mmol) in 50 mL of water is addedN-carboethoxyphthalimide (5.65 g, 25.0 mmol). After 1 hour at roomtemperature, the reaction slurry is filtered, the filtrate stirred, andthe pH adjusted to 1-2 with 4N hydrochloric acid. The mixture is stirredovernight, the resulting slurry is filtered, and the solid washed withwater and dried in vacuo (60° C., <1 mm) to afford 5.32 g (81%) of the2-phthalimido-4-methylpentanoic acid as a white powder: mp 134°-137° C.;1H NMR (DMSO-d₆, 250 M Hz) δ 12.50 (br s, 1H), 8.00-7.80 (m, 4H), 4.79(dd, 1H, J=4.3), 2.28-2.10 (m,1H), 1.94-1.77 (m,1H), 1.51-1.134 (m, 1H),0.89 (d, 3H, J=4.4), 0.86 (d, 3H, J=4.5); 13C NMR (DMSO-d₆) δ 170.8,167.4, 134.8, 131.1, 123.3, 50.2, 36.7, 24.6, 23.0, 20.8. Anal.Calculated for C₁₄ H₁₅ NO₄. Theoretical: C, 64.36; H, 5.74; N, 5.36.Found: C, 64.18; H, 5.73; N, 5.98.

EXAMPLE 22

To a stirred solution of 2-phthalimido-4-methylpentanoic acid (1.32 g,5.0 mmol) in tetrahydrofuran (25 mL) are added carbonyldiimidazole (0.81g, 5.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine followedby 15 mL of tetrahydrofuran. The reaction mixture is stirred at roomtemperature for 1 hour, then 1 mL of concentrated ammonium hydroxide isadded. After 10 minutes, the reaction mixture is diluted with 50 mLwater. The resulting slurry is partially concentrated to remove thetetrahydrofuran and filtered. The solid is washed with water and driedin vacuo (60° C., <1 mm) to afford 1.16 g (89%) of2-phthalimido-4-methylpentanamide as a white powder: mp 173°-176° C.; 1HNMR (DMSO-d₆, 250 MHz) δ 7.95-7.79 (m, 4 H, Ar), 7.61 (br s, 1 H,CONH2), 7.22 (br s, 1 H, CONH2), 4.73-4.60 (m, 1 H), 2.30-2.10 (m, 1 H),1.95-1.80 (m, 1H), 1.45-1.25 (m, 1H); 13C NMR (DMSO-d₆) d: 170.4, 167.7,134.4, 131.5, 123.1, 51.3, 36.4, 24.7, 23.2, 20.6. Anal. Calculated forC₁₄ H₁₆ N₂ O₃. Theoretical: C, 64.60; H, 6.20; N, 10.76. Found: C,64.63; H, 6.11; N, 10.70.

EXAMPLE 23

To a stirred solution of histidine (3.17 g, 20.0 mmol) and sodiumcarbonate (2.23 g, 21 mmol) in 50 mL of water is addedN-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 1.5 hour, thereaction slurry is filtered. The filtrate is stirred and the pH adjustedto 1-2 with 4N hydrochloric acid. The resulting slurry is filtered andthe solid washed with water and dried in vacuo (60° C., <1 mm) to afford3.65 g (64%) of 2-phthalimido-3-(imidazol-4-yl)propionic acid as a whitepowder: mp 280°-285° C.; 1H NMR (DMSO-d₆, 250 M Hz) δ 12.5 (br s, 1H),7.90-7.60 (m, 6H), 6.80(s, 1H), 4.94 (t, 1H, J=7.8), 3.36 (d, 2H,J=7.8); 13C NMR (DMSO-d₆) δ 170.1, 167.1, 134.8, 134.6, 133.2, 131.1,123.2, 116.3, 52.4, 25.8; Anal. Calculated for C₁₄ H₁₁ N₃ O₄.Theoretical: C, 58.95; H, 3.89; N, 14.73. Found: C, 58.80; H, 3.88; N,14.66.

EXAMPLE 24

To a stirred mixture of 3-amino-3-(4-methoxyphenyl)propionic acid (1.95g, 10.0 mmol) and sodium carbonate (1.11 g, 10.5 mmol) in 200 mL ofacetonitrile-water 1:1 is added N-carboethoxyphthalimide (2.26 g, 10.0mmol). After 1 hour, the reaction slurry is filtered. The filtrate isconcentrated to remove the acetonitrile and the pH adjusted to 1-2 with4N hydrochloric acid and stirred over night. The resulting slurry isfiltered and the solid washed with water. The solid is dried in vacuo(60° C., <1 mm) to afford 2.82 g (87%) of3-phthalimido-3-(4-methoxyphenyl)propionic acid as a white powder: mp160°-164° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 12.5 (br s, 1H), 7.95-7.80 (m,4 H), 7.36 (d, 2 H, J=8.7), 6.92 (d, 2 H, J=8.4 Hz), 5.18-5.10 (m, 1 H),3.70-3.15 (m, 2 H); 13C NMR (DMSO-d₆) δ 171.7, 167.6, 158.6, 134.6,131.0, 130.8, 128.3, 123.1, 113.9, 55.0, 49.6, 35.9. Anal. Calculatedfor C₁₈ H₁₅ NO₅. Theoretical: C, 66.46; H, 4.63; N, 4.31. Found: C,66.25; H, 4.65; N, 4.28.

Similarly from 3-amino-3-(3-methoxyphenyl)propionic acid there isobtained 3-phthalimido-3-(3-methoxyphenyl)propionic acid as whitecrystals: mp 111°-115° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 12.5 (br s, 1H),7.94-7.81 (m, 4 H), 7.32-7.23 (m, 1H), 7.02-6.85 (m, 3 H), 5.70-5.60 (m,1 H), 3.77-3.67 (s, 3H), 3.56-3.15 (m, 2 H); 13C NMR (DMSO-d₆) δ 171.6,167.6, 159.2, 140.4, 134.7, 131.0, 129.7, 123.2, 119.0, 112.9, 112.7,54.9, 50.0, 35.8.

Likewise from 3-amino-3-(2-methoxyphenyl)propionic acid there isobtained 3-phthalimido-3-(2-methoxyphenyl)propionic acid as a whitepowder: mp 163°-168° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 12.5 (br s, 1H),7.95-7.80 (m, 4 H), 7.45-6.90 (m, 4H), 6.05-5.92 (m, 1 H), 3.78 (s, 3H)3.55-3.05 (m, 2 H); 13C NMR (DMSO-d₆) δ 171.7, 167.5, 156.1, 134.5,131.0, 128.9, 127.3, 126.1, 123.0, 120.1, 111.0, 55.5, 45.3, 35.1.

By following the procedure of Example 22 utilizing3-phthalimido-3-(4-methoxyphenyl)propionic acid, there is obtained3-phthalimido-3-(4-methoxyphenyl)propionamide as a white powder: mp183°-188° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 7.90-7.75 (m, 4 H, Ar), 7.58(br s, 1 H, CONH₂), 7.38 (d, 2H, J=8.6), 6.91 (d, 3H, J=8.6), 5.73 (t,1H, J=7.8), 3.23(d, 2H, J=7.9); 13C NMR (DMSO-d₆) d: 171.2, 167.6,158.5, 134.5, 131.3, 131.2, 128.4, 123.0, 113.7, 55.0, 49.9, 36.8. Anal.Calculated for C₁₈ H₁₆ N₂ O₄. Theoretical: C, 66.66; H,4.97; N, 8.64.Found: C, 66.27; H, 5.04; N, 8.40.

To a stirred mixture of 3-amino-3-(4-cyanophenyl)propionic acid (3.80 g,20.0 mmol) and sodium carbonate (2.23 g, 21 mmol) in 100 mL of water isadded N-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 2 hour, thereaction slurry is filtered and the pH of the stirred filtrate adjustedto 1-2 with 4N hydrochloric acid. The resulting gel is extracted withethyl acetate (3×30 mL). The extract is dried over magnesium sulfate andconcentrated in vacuo. The crude product is recrystallized from 10%aqueous acetonitrile and then recrystallized from 20% aqueous methanol.The product is dried in vacuo (60° C., <1 mm) to afford 1.5 g (23%) of3-phthalimido-3-(4-cyanophenyl)propionic acid as a white powder: mp134°-137° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 12.5 (br s, 1H), 7.95-7.56 (m,8 H),.5.76 (t, 1 H, J=7.7), 3.57-3.15 (m, 2 H); 13C NMR (DMSO-d₆) δ171.5, 167.6, 144.2, 134.8, 132.6, 131.1, 128.1, 123.3, 118.5, 49.7,35.5.

Like wise from 3-amino-3-(3-cyanophenyl)propionic acid there is obtained3-phthalimido-3-(3-cyanophenyl)propionic acid as a white powder: mp172°-175° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 12.5 (br s, 1H), 8.05-7.51 (m,8 H), 5.82-5.70 (m, 1 H), 3.63-3.20(m, 2 H); 13C NMR (DMSO-d₆) δ 171.5,167.6, 140.3, 134.6 132.0, 131.5, 131.2, 130.7, 129.8, 123.22, 118.5,111.6, 3,3. .49.3 35.6.

EXAMPLE 27

By following the procedure of Example 22 utilizing3-phthalimido-3-(4-cyanophenyl)propionic acid, there is obtained3-phthalimido-3-(4-cyanophenyl)propionamide as a white powder: 1H NMR(DMSO-d₆, 250 MHz) δ 8.05-7.50 (m, 9 H), 9-6.97 (s, 1 H), 5.87-5.72 (m,1 H), 3.44-3.12 (m, 2 H); 13C NMR (DMSO-d₆) 5 170.8, 167.6, 144.6,134.6, 132.4, 131.1, 127.9, 123.2, 118.5, 110.3, 49.8,36.4.

Similarly from 3-phthalimido-3-(3-cyanophenyl) propionic acid (1.60 g,5.0 mmol), there is obtained 3-phthalimido-3-(3-cyanophenyl)propionamideas a white powder: mp 217°-220° C.; 1H NMR (DMSO-d₆, 250 MHz) δ8.05-7.40 (m, 9 H), 6.99 (br s, 1 H), 5.90-5.75 (m, 1H), 3.50-3.10 (m,2H); 13C NMR (DMSO-d₆) d: 171.0, 167.7, 140.8, 134.6, 132.2, 131.5,131.4, 130.8, 129.9, 123.2, 118.7, 111.5, 49.7, 36.7.

EXAMPLE 28

To a stirred solution of phenyl isocyanate (2.2 mL, 2.4 g, 20 mmol) inacetonitrile (40 mL) is added a solution of L-glutamine (2.92 g, 20.0mmol) and sodium hydroxide (20 mmol) in water (20 mL). The reactionmixture is stirred for 45 hours, partially concentrated to remove theacetonitrile, and washed with ethyl acetate (2×25 mL). The pH of theaqueous layer is adjusted to 1-2 with 4N hydrochloric acid, theresulting thick slurry filtered, and the solid washed with water andair-dried to afford 4.70 g (89%) yield of2-(N-phenyluriedo)-4-carbamoylbutyric acid as a white powder.

2-(N-phenyluriedo)-4-carbamoylbutyric acid (2.00 g, 7.54 mmol) andcarbonyldiimidazole (1.24 g, 7.95 mmol) in tetrahydrofuran (30 mL) areheated at reflux for 16 hours. The reaction mixture is concentrated andthe residue slurried in water (25 mL), the slurry filtered, and thesolid washed with water and air-dried to afford 0.63 g ofN-phenyl-N'-(1,6-dioxopiperidin-2-yl)urea. After sitting, filtration ofthe filtrate afforded 0.70 g (38%) of the product as a white flocculentpowder: 1H NMR (DMSO-d₆) δ 8.51 (s, 1 H, CONHCO), 7.6-7.2 (m, 6 H, Ar,ArNH), 6.83 (s, 1 H, NHCH), 4.26 (t, 1 H, CHCO), 2.4-1.8 (m, 4 H,CH2CH2); 13C NMR (DMSO-d₆) δ 173.2, 155.6, 132.2, 128.7, 127.7, 126.7,55.7, 29.8, 27.2. Anal. Calculated for C₁₂ H₁₃ N₃ O₃. Theoretical: C,58.29; H, 5.29; N, 16.99. Found: C, 58.12; H, 5.17; N, 17.02.

EXAMPLE 29

To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acidmethyl ester hydrochloride (1.50 g, 6.1 mmol) and sodium carbonate(90.65 g, 6.1 mmol) in 40 mL of water was added N-carboethoxyphthalimide(1.34 g, 6.1 mmol) in 12 mL of acetonitrile. The reaction mixture wasstirred at room temperature for 1 hour. The reaction mixture waspartially concentrated and this mixture was stirred for 72 hours. Theresulting slurry was filtered and the solid was washed with copiousamount of water. The solid was dried in vacuo (30° C., <1 mm) to afford1.70 g (50%) of methyl 3-phthalimido-3-(4-methoxyphenyl)propionate as awhite powder. mp 65°-66° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 7.83-7.91 (m,4H), 6.88-7.3 (m, 4H), 5-80 (dd, 1H, J=7.5, 2.5), 3.72 (S, 3H), 3.54 (3,3H), 3.2-3.6 (m, 2H); 13C NMR (DMSO-d₆) δ 170.7, 167.5, 158.7, 134.6,131.0, 130.5, 128.3, 123.2, 113.9, 55.0, 51.5, 49.4, 35.4. Anal. Calcdfor C₁₉ H₁₇ NO₅ : C, 67.25; H, 5.05; N, 4.13; Found: C, 66.96; H, 5.00;N, 4.11.

EXAMPLE 30

To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid ethylester hydrochloride (1.00 g, 3.85 mmol) and sodium carbonate (0.41g,3.85 mmol) in 40mL of water was added N-carboethoxyphthalimide (0.84 g,3.85 mmol) in 10 mL of acetonitrile. The reaction was complete in onehour by TLC. The reaction mixture was partially concentrated to removethe acetonitrile. To the resulting mixture was added 0.5 mL of ethylether and the mixture was stirred for 1 hour at room temperature. Theresulting slurry was filtered and the solid was washed with copiousamounts of water. The solid was air-dried overnight to afford 1.02 g(75%) of ethyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a whitegum: mp 32° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 7.86 (m, 4H), 6.90-7.37 (M,4H), 5.66 (dd, 1H J1=7.5, J2=2.5), 4.00 (d, 2H, J=7.5), 3.3-3.6 (M, 2H),1.04 (t, 3H, J=7.5 Hz); 13C (DMSO-d₆) δ 170.1, 167.5, 158.7, 134.7,131.0, 130.5, 128.3, 123.2, 113.88, 60.1, 55.0, 49.5, 35.7, 13.8. Anal.Calcd for C₂₀ H₁₉ NO₅ : C, 67.98; H, 5.42; N, 3.90; Found C, 67.78; H,5.30; N, 3.92.

EXAMPLE 31

To a stirred solution of 3-amino-3-phenylpropionic acid methyl esterhydrochloride (0.50 g, 2.3 mmol) and sodium carbonate (0.25 g, 2.3 mmol)in 10 mL of water was added N-carboethoxyphthalimide (0.51 g, 2.3 mmol)in 7 mL of acetonitrile. The reaction progress was monitored by TLC(ethyl acetate/hexane; 1:2) which showed that the reaction was completein one hour. The reaction mixture was partially concentrated to removethe acetonitrile. The resulting slurry was filtered and the solid waswashed with 20 mL of water. The solid was dried in vacuo (60° C., <1 mm)to afford 280 mg (39.4%) of methyl 3-phthalimido-3-phenylpropionate as awhite powder: mp 75°-76° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 7.26-7.83 (m,9H), 5.68-5.75 (m, 1H), 3.55 (S, 3H), 3.37-3.66 (m, 2H); 13C NMR(DMSO-d₆) δ 170.7, 167.6, 138.6, 134.7, 131.0, 128.6, 127.8, 126.9,123.3, 51.6, 49.9, 35.3. Anal. Calcd for C₁₈ H₁₅ NO₄ : C, 69.89; H,4.89; N, 4.53; Found: C, 69.69; H, 4.83; N, 4.49.

EXAMPLE 32

To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acidpropyl ester hydrochloride (1.50 g, 5.52 mmol) and sodium carbonate(0.59g, 5.52 mmol) in 50 mL of water was added N-carboethoxy-phthalimide(1.21 g, 5.52 mmol) in 12 mL of acetonitrile. The reaction was completein one hour. The acetonitrile was removed in vacuo and 5 mL of ether wasadded to the mixture, which was stirred overnight at room temperature.The resulting slurry was filtered and the solid was washed with 60 mL ofwater. The solid was dried in vacuo (24° C., <1 mm) to afford 1.69 g(83.2%) of propyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a whitepowder: mp 51.2°-52.8° C.; 1H NMR (DMSO-d₆ 250 MHz) δ 7.86 (m, 4H),6.92-7.33 (m, 4H), 5.66 (dd, 1H, J=7.5, 2.5 Hz), 3.90 (t, 2H, J=5 Hz),3.72 (S, 3H), 3.3-3.63 (m, 2H), 1.42 (hex, 2H, J=7.5 Hz), 0.75 (t, 3H,J=7.5 Hz); 13C (DMSO-d₆) δ 170.2, 167.5, 158.7, 134.7, 131.0, 130.5,128.3, 123.2, 113.9, 65.6; 55.0, 49.5, 21.3, 9.98. Anal. Calcd for C₁₉H₁₇ NO₅ :=C, 68.65; H, 5.76; N, 3.81; Found=C, 68.42; H, 5.49; N, 3.76.

EXAMPLE 33

A stirred mixture of phenylglycine (1.51 g, 10.0 mmol) and phthalicdicarboxaldehyde (1.34 g, 10.0 mmol) in 10 mL of acetic acid undernitrogen was heated to reflux for 10 minutes. The resulting mixture wasallowed to cool overnight and the resulting slurry filtered to afford1.56 g of crude product. The crude product was recrystallized fromacetic acid to afford after drying in vacuo (<1 mm, 60° C.) 0.95 g (36%)of α-(1-oxoisoindolin-2-yl)phenylacetic acid as a white powder: 1H NMR(DMSO-d₆, 250 MHz) 7.85-7.30 (m, 9 H, Ar), 6.01 (s, 1 H, CH), 4.64 (d,J=17.4 Hz, 1 H), 3.92 (d, J=17.4 H, 1 H); 13C NMR (DMSO-d₆) 171.2,167.4, 142.0, 134.6, 131.6, 131.3, 128.9, 128.7, 128.4, 127.9, 123.6,122.9, 57.9, 47.6; Anal. Calcd for C₁₆ H₁₃ NO₃ 0.13 H₂ O. Theory: C,71.29; h, 4.95; N, 5.20. Found: C, 71.29; h, 4.86; N, 5.26.

EXAMPLE 34

A mixture of α-(1-oxoisoindolin-2-yl)phenylacetic acid (0.50 g, 1.87mmol) and carbonyl diimidazole (CDI, 0.319 g, 1.96 mmol) in 20 mL oftetrahydrofuran under nitrogen was stirred for 2.5 h, then 0.3 mL of 15Nammonium hydroxide was added. The resulting mixture was stirred for 20minutes, concentrated to an oil and diluted with 25 mL of water. Themixture was stirred and the resulting slurry filtered to afford afterdrying 0.38 g (76%) of α-(1-oxoisoindolin-2-yl)phenylacetamide as awhite powder: 1H NMR (DMSO-d₆, 250 MHz) 8.10-7.20 (m, 11 H), 6.03 (s, 1H), 4.80 (d, J=17.7 Hz, 1 H), 3.90 (d, J=17.7 Hz, 1 H); 13C NMR(DMSO-d₆) 167.4, 142.2, 136.0, 131.5, 131.4, 128.7, 128.5, 128.0, 127.7,123.4, 122.8, 57.5, 48.0; Anal. Calcd for C₁₆ H₁₄ N₂ O₂ : Theory C,72.17; H, 5.30; N, 10.52. Found: C, 72.00; H, 5.27; N, 10.56.

EXAMPLE 35

By following the procedure of Example 33 utilizing d,1-phenylalaninethere is obtained, without recrystallization, 4.46 g (79%) of3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid as an off-white solid:1H NMR (DMSO-d₆, 250 MHz) 13.16 (br s,1 H, COOH), 7.70-7.05 (m, 9 H,Ar), 5.17 (dd, J=11, 4.8 Hz, 1 H), 4.45 (s, 2 H, benzylic H), 3.42 (dd,J=14.6, 4.8 Hz, 1 H), 3.22 (dd, J=14.6, 11 Hz, 1 H); 13C NMR (DMSO-d₆)171.8, 167.7, 141.8, 137.4, 131.5, 131.4, 128.4, 128.3, 127.8, 126.4,123.4, 122.8, 54.7, 47.2, 34.6; Anal. Calcd for C₁₇ H₁₅ NO₃ : Theory C,72.58; H, 5.37; N, 4.98. Found: C, 72.60; H, 5.33; N, 4.91.

EXAMPLE 36

By following the procedure of Example 34 utilizing3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid there is obtained 1.13 g(81%) of 3-phenyl-2-(1-oxoisoindolin-2-yl)propionamide as a fine whitepowder: 1H NMR (DMSO-d₆, 250 MHz) 7.90-7.05 (m, 11 H, Ar and CONH2),5.16 (dd, J=11, 5Hz, 1 H), 5.71 (d, J=18Hz, 1 H), 5.45 (d, J=18 Hz, 1H), 3.33 (dd, J=15, 5 Hz, 1 H), 3.11 (dd, J=11, 15 Hz, 1 H); 13C NMR(DMSO-d₆) 172.0, 167.6, 142.0, 137.6, 131.7, 131.3, 128.4, 128.2, 127.6,126.3, 123.3, 122.7, 54.6, 47.2, 35.3; Anal. Calcd for C₁₇ H₁₆ N₂ O₂ :Theory C, 72.84; H, 5.75; N, 9.99. Found: C, 72.72; H, 5.76; N, 9.86.

EXAMPLE 37

By following the procedure of Example 33 utilizing3-amino-3-phenylpropionic acid there is obtained 0.8 g of crude product.The filtrate was then concentrated and the residue slurried in ethylacetate to afford an additional 1.39 g of crude product. The combinedcrude products were recrystallized from ethyl acetate to afford 1.52(58%) of 3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid as fine whitecrystals: 1H NMR (DMSO-d₆, 250 MHz ) 12.44 (br s, 1 H, CO₂ H), 7.80-7.15(m, 9 H, Ar), 5.79 (overlapping dd, 1 H), 4.54 (d, J=17.6 Hz, 1 H), 4.15(d, J=17.6 Hz, 1 H), 3.35-3.0 (m, 2 H); 13C NMR (DMSO-d₆) 171.8, 166.9,141.6, 139.3, 132.0, 131.4, 128.6, 127.9, 127.6, 127.0, 123.4, 122.8,51.3, 46.3, 36.6; Anal. Calcd for C₁₇ H₁₅ NO₃ : Theory C, 72.58; H,5.37; N, 4.90. Found: C, 72.23; H, 5.29; N, 4.90.

EXAMPLE 38

To a stirred solution of 3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid(0.703 g, 2.50 mmol) in 15 mL of tetrahydrofuran under nitrogen wasadded carbonyldiimidazole (0.438 g, 2.70 mmol), and a few crystals of4-N,N-dimethylaminopyridine DMAP!. The reaction mixture was stirred for1.5 hours and then 0.25 mL of 15N ammonium hydroxide was added. After 20minutes, the reaction mixture was concentrated in vacuo and the residueslurried in water. The resulting solid was isolated by filtration anddried in vacuo to afford 0.58 g (80%) of crude product as an off-whitepowder. The crude product was recrystallized from ethanol to afford0.403 g (57%) of 3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide as whiteprisms: 1H NMR (DMSO-d₆, 250 MHz) 7.8-7.2 (m, 10 H), 6.92 (br s, 1 H),5.81 (overlapping dd, 1 H) 4.59 (d, J=17.5 Hz, 1 H), 4.16 (d, J=17.5 Hz,1 H), 3.1-2.8 (m, 2 H); 13C NMR (DMSO-d₆) 171.3, 167.0, 140.7, 132.2,131.4, 128.6, 127.9, 127.5, 126.9, 123.5, 122.8, 51.5, 46.3, 37.9; Anal.Calcd for C₁₇ H₁₆ N₂ O₂ : Theory C, 72.84; H, 5.75; N, 9.99. Found: C,72.46; H, 5.68; N, 9.91.

EXAMPLE 39

By following the procedure of Example 33 utilizing3-amino-3-(4-methoxyphenyl)propionic acid there is obtained 1.52 g ofcrude product as an off white solid from the reaction mixture. Thefiltrate was concentrated and the residue slurried in 25 mL of ethylacetate to afford after filtration an additional 1.27 g (41%) of crudeproduct as a pale green powder. The combined crude products wererecrystallized from 280 mL of ethyl acetate to afford after drying 1.69g (55%) of 3-(4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid asan off-white solid: 1H NMR (DMSO-d₆, 250 MHz); 13C NMR (DMSO-d₆); Anal.Calcd for C₁₈ H₁₇ NO₄ : Theory C, 69.44; H, 5.50; N, 4.50. Found: C,69.33; H, 5.45; N, 4.49.

EXAMPLE 40

By following the procedure of Example 38 utilizing3-(4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid there isobtained 0.49 g (82%) of crude product. The crude product wasrecrystallized from ethyl acetate (40 mL) to afford 0.27 g (45%) of3-(4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide as whiteneedles: 1H NMR (DMSO-d₆, 250 MHz) 7.8-7.4 (m, 5 H), 7.29 (d, 2 H, J=9Hz), 6.91 (d, 2 H, J=9 Hz), 5.78 (t, 1 H, J=8Hz), 4.55 (d, 1 H,J=17.5Hz), 4.11 (d, J=17.5 Hz, 1 H), 3.72 (s, 3 H), 3.05-2.75 (m, 2 H);13C NMR (DMSO-d₆) 171.2, 166.8, 158.4, 141.6, 132.2, 131.8, 131.2,128.1, 127.8, 123.3, 122.7, 113.8, 55.0, 51.0, 46.1; Anal. Calcd forC18H18N2O3-0.38 H₂ O: Theory C, 68.58; H, 5.99; N, 8.80. Found: C,68.58; H, 5.86; N, 8.80.

EXAMPLE 41

The procedure of Example 33 is followed utilizing3-amino-3-(3,4-dimethoxyphenyl)propionic acid with the followingexceptions. The reaction mixture (solution) was concentrated to a thickoil which was diluted with 10 mL of ethyl acetate. The resulting slurrywas filtered, the solid washed with ethyl acetate and then dried invacuo (>1 mm, 60° C.) to afford 2.77 g (81%) of3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid as awhite powder: mp 146.5-148.5 C; 1H NMR (DMSO-d₆, 250 MHz) 12.34 (br s, 1H, CO2H), 7.8-7.4 (m, 4 H), 7.1-6.8 (m, 3 H), 5.85-5.65 (m, 1 H), 4.51(d, 1 H, J=18 Hz), 4.13 (d, 1 H, J=18 Hz), 3.75 (s, 3 H), 3.73 (s, 3 H),3.3-3.0 (m, 2 H); 13C NMR (DMSO-d₆) 171.8, 166.7, 148.7, 148.3, 141.6,132.1, 131.6, 131.3, 127.8, 123.4, 122.7, 119.2, 111.7, 111.2, 55.5,55.4, 46.3, 36.8; Anal. Calcd for C₁₉ H₁₉ NO₅ : Theory C, 66.85; H,5.61; N, 4.10. Found: C, 67.19; H, 5.57; N, 3.73.

EXAMPLE 42

The procedure of Example 38 is followed utilizing3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid with thefollowing changes. The crude product did not precipitate from waterimmediately. The product crystallized from aqueous solution upon sittingfor several days after an ether wash to afford 0.26 g (22%) of3-(3,4-dimethoxy-phenyl)-3-(1-oxoisoindolin-2-yl)propionamide as whiteneedles: 1H NMR DMSO-d₆, 250 MHz) 7.8-7.4 (m, 5H), 7.1-6.85 (m, 4 H),5.76 (m, 1 H), 4.57 (d, 17.6 Hz, 4.15 (d, J=17.6 Hz, 1 H), 3.74 (s, 3H), 3.72 (s, 3 H), 3.1-2.8 (m, 2 H); 13C NMR (DMSO-d₆) 171.2, 166.8,148.6, 148.1, 141.6, 132.2, 132.2, 131.2, 127.8, 123.4, 122.7, 119.0,111.6, 111.0, 55.4, 51.4, 46.2, 37.9; Anal. Calcd for C₁₉ H₂ 0N₂ O₄ :Theory C, 67.05; H, 5.92; N, 8.23. Found: C, 66.74; H, 5.88; N, 8.02.

EXAMPLE 43

To a stirred solution of 3-amino-3-(3,4-diethoxyphenyl)propionic acid(1.03 g, 4.07 mmol) and sodium carbonate (0.453 g, 4.27 mmol) in a 1/1mixture of 150 mL of acetonitrile/water (heated to 45° C. to dissolve)was added N-carbethoxyphthalimide (0.89 g, 4.07 mmol). The reactionmixture was stirred 1 hour, then partially concentrated in vacuo toremove the acetonitrile to afford a pale yellow solution. The stirredsolution was acidified to pH 0-1 with 4N hydrochloric acid to form agum. The mixture was stirred overnight. The gum had not solidified and 1mL of ether was added to mixture. The gum solidified on stirring and theslurry was filtered and the solid dried to afford 1.94 g (94%) of3-(3,4-diethoxyphenyl)-3-phthalimidopropionic acid as a yellow solid: 1HNMR (DMSO-d₆, 250 MHz) 12.41 (br s, 1 H, COOH), 8.10-7.75 (m, 4 H, Ar),7.15-6.85 (m, 3 H, Ar), 5.62 (overlapping dd, 1 H), 4.20-3.90 (m, 4 H, 2OCH2), 3.51 (dd, 1 H, J=9 Hz), 3.25 (dd, 1 H, J=16.5, 7 Hz), 1.5-0.9 (m,6 H, 2 CH3) 13C NMR (DMSO-d₆) 1717, 167.6, 147.9, 147.8, 134.6, 131.3,131.0, 123.1, 119.4, 113.2, 112.7, 63.8, 63.7, 50.0, 36.0, 14.6, 14.6;Anal. Calcd for C₂₁ H₂₁ NO₆ : Theory C, 65.79; H, 5.52; N, 3.65. Found:C, 65.54; H, 5.55; N, 3.62.

EXAMPLE 44

The procedure of Example 43 was followed with the following changes. Thereaction mixture concentrated in vacuo and to an oil which was dilutedwith water (20 mL) and ether (1 mL) and the mixture stirred overnight.The resulting slurry was filtered and the solid dried in vacuo to afford0.41 g (41%) of crude product. The crude product was recrystallized fromethyl acetate to afford 0.265 g (27%) of3-(3,4-diethoxyphenyl)-3-phthalmidopropionamide as white crystals: 1HNMR (DMSO-d₆, 250 MHz) 8.00-7.60 (m,4 H, Ar),7.55 (br s, 1 H, NH), 7.03(br s, 1 H, NH), 6.89 (br s, 3 H, Ar), 5.66 (t, 1 H, J=8 Hz), 4.15-3.85(m, 4 H), 3.3-3.05 (m, 2 H), 1.5-1.15 (m, 6 H); 13C NMR (DMSO-d₆) 171.2,167.6, 147.8, 147.6, 134.5, 131.6, 131.2, 123.0, 119.5, 113.0, 112.7,63.7, 63.6, 50.2, 36.9, 14.6, 14.6; Anal. Calcd for C₂₁ H₂₂ N₂ O₅ :Theory C, 65.96 H, 5.80; N, 7.33. Found: C, 65.45; H, 5.55; N, 7.20.

EXAMPLE 45

To a stirred solution of sodium carbonate (1.45 g, 13.7 mmol) in 500 mLof water-acetonitrile (1:1, v/v) was added3-amino-3-(4-propoxyphenyl)propionic acid (3.05 g, 13.7 mmol) as asolid. The mixture was warmed to 30°-40° C. to dissolve the solids. Thereaction mixture was allowed to cool to room temperature andN-carboethoxyphthalimide (3.00 g, 13.7 mmol) was added and the reactionmixture was stirred for one hour at room temperature. The reactionmixture was then partially concentrated to remove the acetonitrile andthe pH of the resulting solution was adjusted to approximately 3 with 4Nhydrochloric acid. The resulting slurry was stirred overnight and thenfiltered and the solid was washed with copious amounts of water. Thesolid was dried in vacuo (60° C., <1 mm) to afford 3.64 g (75%) of3-phthalimido-3-(4-propoxyphenyl)propionic acid as a white powder: mp142.5°-143.6° C., 1H NMR(DMSO-d₆, 250 MHz) δ 12.43 (br s, 1 H),7.80-7.95 (m, 4 H), 7.34 (d, 2 H, J=9 Hz), 6.89 (d, 2 H, J=9 Hz), 5.63(overlapping dd, 1 H), 3.88 (t, 2 H, J=7 Hz), 3.45 (dd, 1 H, J1=9 Hz,J2=16.5 Hz), 3.30 (dd, 1 H, J1=7 Hz, J2=16.5 Hz), 1.60-1.85 (m, 2 H),0.95 (t, 3 H, J=7 Hz); 13C (DMSO-d₆) δ 171.8, 167.6, 158.6, 134.7,131.1, 130.8, 128.3, 123.2, 114.4, 68.9, 49.7, 36.0, 22.0, 10.3; Anal.Calcd. for C₂₀ H₁₉ NO₅. Theoretical: C, 67.98; H, 5.42; N, 3.96. Found:C, 67.90; H, 5.40; N, 4.00.

EXAMPLE 46

To a stirred solution of 3-phthalimido-3(4-propoxyphenyl)propionic acid(1.41 g, 4.0 mmol) in 25 mL of under nitrogen was addedcarbonyldiimidazole (0.68 g, 4.2 mmol) followed by a catalytic amount ofdimethylaminopyridine. The mixture was stirred for 45 minutes at roomtemperature. To the reaction mixture was then added concentratedammonium hydroxide (0.29 mL, 4.4 mmol) and the reaction mixture wasstirred for 30 minutes at room temperature. The mixture was then dilutedwith 10 mL of water and the tetrahydrofuran was removed in vacuo. Theresulting slurry was filtered and the solid was washed with copiousamounts of water. The solid was dried in vacuo (60° C., <1 mm) to afford1.2 g of crude product. The crude product was purified by dissolving in200 mL of ethyl acetate, stirring for 3 h and then concentrating to an80 mL volume. The resulting slurry was filtered and the solid was washedwith ethyl acetate (2×20 mL). The solid was air-dried to afford 0.513 g(36%) of 3-phthalimido-3-(4-propoxyphenyl)propionamide as a whitepowder: mp 109.5°-110.4° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 7.85 (br s, 4H), 7.55 (br s, 1 H), 7.33 (d, 2 H, J=8 Hz), 6.75-7.00 (m, 3 H), 5.69(t, 1 H, J=8 Hz), 3.88 (t, 2 H, J=6 Hz), 3.10-3.30 (m, 2 H), 1.60-1.80(m, 2 H), 0.95 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d₆) δ 171.2, 167.7,158.0, 134.5, 131.23, 131.19, 128.4, 123.1, 114.3, 68.9, 49.9, 36.9,22.0, 20.4, 10.4; Anal. Calcd. for C₂₀ N₂ O₄ 0.37 H₂ O. Theoretical: C,66.90; H, 5.61; N, 7.80. Found: C, 66.90; H, 5.52; N, 7.75.

EXAMPLE 47

To 40 mL of stirred ethanol at 0° C. under nitrogen was slowly addedthionyl chloride (3.3 mL, 45 mmol) followed by addition of3-amino-3-(3-pyridyl)propionic acid (2.65 g, 15 mmol). The reactionmixture was allowed to slowly warm to room temperature and then refluxedfor 3 hours. After 2 hours at reflux all of the solid had dissolved. Thereaction mixture was allowed to cool to room termperature and stirredovernight. The slurry was filtered and the solid was washed with copiousamounts of ethanol. The solid was dried in vacuo (60° C., <1 mm) toafford 3.17 g (79%) of ethyl 3-amino-3-(3-pyridyl)propionatehydrochloride as a white powder: 1H NMR (DMSO-d₆, 250 MHz) δ 9.32 (br s,3 H), 9.21 (br s, 1 H), 8.87-8.95 (m, 2 H), 8.09-8.14 (m, 1 H), 4.93 (brs, 1 H), 3.90-4.15 (m, 2 H), 3.20-3.38 (m, 2 H), 1.11 (t, 3 H, J=7 Hz);13C NMR (DMSO-d₆) δ 168.8, 144.5, 142.8, 142.6, 136.2, 126.7, 60.7,47.9, 37.2, 13.9.

EXAMPLE 48

By following the procedure of Example 30 but utilizing ethyl3-amino-3-(3-pyridyl)propionate hydrochloride, there is obtained ethyl3-phthalimido-3-(3-pyridyl)propionate as a white powder (0.43 g, 71%):mp 72.3°-72.8° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 8.45-8.70 (m, 2 H),7.80-8.00 (m, 5 H), 7.35-7.45 (m, 1 H), 5.78 (dd, 1 H, J1=6.5 Hz, J2=9.5Hz), 4.01 (q, 2 H, J=7 Hz), 3.62 (dd, 1 H, J1=6.5 Hz, J2=16.4 Hz), 3.41(dd, 1 H, J1=9.5 Hz, J2=16.4 Hz), 1.05 (t, 3 H, J=7 Hz); 13C NMR(DMSO-d₆) δ 169.9, 167.5, 148.96, 148.4, 134.9, 134.7, 134.0, 131.0,123,6, 123.3, 60.3, 47.9, 35.2, 13.8; Anal. Calcd. for C18H16N2O4.Theoretical: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.51; H, 4.94; N,8.56.

EXAMPLE 49

By following the procedure of Example 45 but utilizing3-amino-3-(3,4-dimethoxyphenyl)propionic acid,3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid was isolated as awhite powder (5.30 g, 75%): 1H NMR (DMSO-d₆, 250 MHz) δ 12.44 (br s,1H), 7.70-8.00 (m, 4 H), 6.85-7.10 (m, 3 H), 5.63 (dd, 1 H, J1=7 Hz, J2=9Hz), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.53 (dd, 1 H, J1=9 Hz, J2=16.5 Hz),3.26 (dd, 1 H, J1=7 Hz, J2=16.5 Hz), 13C NMR (DMSO-d₆) δ 171.8, 167.7,148.6, 148.4, 134.7, 131.3, 131.1, 123.2, 119.3, 111.7, 111.0, 55.48,55.46, 50.1, 36.1.

EXAMPLE 50

By following the procedure of Example 46 but utilizing3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid,3-phthalimido-3-(3,4-dimethoxyphenyl)propionamide was isolated as awhite powder (0.314 g, 52%): mp 188.8°-190.0° C.; 1H NMR (DMSO-d₆, 250MHz) δ 7.7-8.0 (m, 4 H), 7.54 (br s, 1 H), 6.7-7.1 (m, 4 H), 5.67 (t, 1H, J=8 Hz), 3.73 (s, 3 H), 3.72 (s, 3 H), 3.20 (d, 2 H, J=8 Hz); 13C NMR(DMSO-d₆) δ 171.2, 167.7, 148.5, 134.7, 134.5, 131.7, 131.2; 123.1,119.4, 111.6, 111.2, 55.5, 50.3, 37.0; Anal. Calcd. for C₁₉ H₁₈ N₂ O₅.Theoretical: C, 64.40; H, 5.12; N, 7.91. Found: C, 64.01; H, 5.14; N,7.64.

EXAMPLE 51

The procedure of Example 47 was followed starting with3-amino-3-(3,4-dimethoxyphenyl)propionic acid except the reaction wasrun at room temperature. Ethyl 3-amino-3-(3,4-dimethoxyphenyl)propionatewas isolated as a white powder (2.04 g, 88%): 1H NMR (DMSO-d₆, 250 MHz)δ 8.75 (br s, 3 H), 7.30-7.35 (m, 1 H), 6.90-7.05 (m, 2 H), 4.50 (dd, 1H, J1=6 Hz, J2=9 Hz), 3.90-4.10 (m, 2 H), 3.77 (s, 3 H), 3.75 (s, 3 H),3.19 (dd, 1 H, J1=6 Hz, J2=16 Hz), 2.98 (dd, 1 H, J1=9 Hz, J2=16 Hz),1.10 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d₆) δ 169.1, 149.0, 148.6, 128.9,120.1, 111.4, 60.4, 55.6, 55.5, 50.9, 38.7, 13.9.

EXAMPLE 52

The procedure of Example 30 was followed utilizing ethyl3-amino-3-(3,4-dimethoxyphenyl)propionate. The reaction mixture wasconcentrated and the residue was dissolved in 20 mL of ethyl acetate andwashed with water (3×20 mL). The organic phase was dried over sodiumsulfate and then concentrated to afford 0.31 g (40%) of ethyl3-phthalimido-3-(3,4-dimethoxyphenyl)propionate as a yellow oil: 1H NMR(DMSO-d₆, 250 MHz) δ 7.80-7.95 (m, 4 H), 7.04 (s, 1 H), 6.85-6.98 (m, 2H), 5.65 (dd, 1 H, J1=6 Hz, J2=10 Hz), 4.00 (q, 2 H, J=7 Hz), 3.74 (s, 3H), 3.73 (s, 3 H), 3.60 (dd, 1 H, J1=10 Hz, J2=16 Hz), 3.32 (dd, 1 H,J1=6 Hz, J2=16 Hz), 1.05 (t, 3 H, J=7 Hz), 13C NMR (DMSO-d₆) δ 170.2,167.5, 148.58, 148.54, 134.7, 131.1, 1309, 123.2, 119.2, 111.6, 111.0,60.1, 55.5, 50.0, 35.9, 13.9; Anal. Calcd. for C₂₁ H₂₁ NO₆. Theoretical:C, 65.79; H, 5.52; N, 3.65. Found: C, 65.13; H, 5.73; N, 3.61.

EXAMPLE 53

By following the procedure of Example 46 utilizing3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid and amylamine (1.0equiv) there is obtained 2.15 g (84%) of crude product. The crudeproduct was dissolved in 150 mL of ethyl acetate and then 50 mL of etherwas added and the mixture stirred for 1 hour. The resulting slurry wasfiltered and the solid dried in vacuo to afford 1.28 g (50%) yield of3-phthalimido-3-(3,4-dimethoxyphenyl)propionic amylamide as a whitepowder: mp 140.5°-142.1° C.; 1H NMR (DMSO-d₆, 250 MHz), δ 8.05 (t, 1 H,J=5 Hz), 7.85 (m, 4 H), 7.03 (br s, 1 H), 6.90 (m, 3 H), 5.68 (t, 1 H,J=8 Hz), 3.73 (s, 3 H), 3.71 (s, 3 H), 3.19 (d, 2 H, J=8 Hz), 2.8-3.1(m, 2 H), 0.9-1.3 (m, 6 H), 0.74 (m, 3 H); 13C NMR (DMSO-d₆) δ 168.8,167.7, 148.5, 148.3, 134.5, 131.5, 131.2, 123.1, 119.5, 111.6, 111.1,55.4, 50.6, 38.2, 37.4, 28.7, 28.3, 21.7, 13.7; Anal. Calcd. for C₂₄ H₂₈N₂ O₅. Theoretical: C, 67.9; H, 6.65; N, 6.60. Found: C, 67.84; H, 6.70;N, 6.57.

EXAMPLE 54

By following the procedure of Example 46 utilizing3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid and benzylamine (1.0equiv) there is obtained 2.45 g (92%) of3-phthalimido-3-(3,4-dimethoxyphenyl)propionic benzylamide as whitepowder: mp 208.4°-209.8° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 8.60 (t, 1, J=6Hz), 7.78-7.92 (m, 4 H), 6.85-7.20 (m, 8 H), 5.73 (t, 1 H, J=8 Hz),4.10-4.30 (m, 2 H), 3.73 (s, 3 H), 3.72 (s, 3 H), 3.20-3.45 (m, 2 H);13C NMR (DMSO-d₆) δ 169.1, 167.7, 148.5, 148.3, 139.2, 134.5, 131.4,131.2, 127.9, 126.7, 123.1, 119.5, 111.5, 111.2, 101.9, 55.4, 55.37,50.6, 41.7, 37.4; Anal. Calcd. for C₂₆ H₂₄ N₂ O₅. Theoretical: C, 70.26;H, 5.44; N, 6.30. Found: C, 70.12; H, 5.53; N, 6.25.

EXAMPLE 55

The procedure of Example 46 was followed utilizing3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid and ethylamine (1.0equiv). After the reaction mixture was concentrated, the residue wasdiluted with 20 mL of water and 1 mL of ether. The mixture was stirredfor 1 hour to afford a slurry. The slurry was filtered and the soliddried in vacuo to afford 0.66 g (77%) of3-phthalimido-3-(3,4-dimethoxyphenyl)propionic ethylamide compound as awhite powder: mp 131.0°-132.5° C.; 1H NMR (DMSO-d₆, 250 HMz) δ 8.08 (t,1 H, J=5 Hz), 7.78-7.95 (m, 4 H), 7.03 (s, 1 H), 6.85-7.00 (m, 2 H),5.69 (t, 1 H, J=8 Hz), 3.74 (s, 3 H), 3.72 (s, 3 H), 3.18 (d, 2 H, J=8Hz), 2.98 (m, 2 H), 0.88 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d₆) δ 168.8,167.7, 148.5, 148.2, 134.5, 131.6, 131.2, 123.1, 119.4, 111.6, 111.1,55.5, 50.5, 37.3, 33.2, 14.5; Anal. Calcd. for C₂₁ H₂₂ N₂ O₅.Theoretical: C, 65.96; H, 5.80; N, 7.33. Found: C, 65.85; H, 5.84; N,7.24.

EXAMPLE 56

The procedure of Example 45 was followed utilizing3-amino-3-(4-ethoxyphenyl)propionic acid.3-Phthalimido-3-(4-ethoxyphenyl)propionic acid was isolated as a whitepowder (2.52 g, 74%): mp 169.2°-171.1° C.; 1H NMR (DMSO-d₆, 250 MHz) δ7.75-8.00 (m, 4 H), 7.34 (d, 2 H, J=8.7 Hz), 6.89 (d, 2 H, J=8.7 Hz),5.64 (overlapping dd, 1 H), 3.98 (q, 2 H, J=7 Hz), 3.48 (dd, 1 H, J1=9Hz, J2=16.5 Hz), 3.26 (dd, 1 H, J1=7 Hz, J2=16.5 Hz), 1.30 (t, 3 H, J=7Hz); 13C NMR (DMSO-d₆) δ 171.8, 167.7, 158.0, 134.7, 131.1, 130.8,128.4, 123.2, 114.4, 63.0, 49.7, 36.1, 14.6; Anal. Calcd. for C₁₉ H₁₇NO₅. Theoretical: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.05, H, 4.93;N, 4.17.

EXAMPLE 57

By following the procedure of Example 46 utilizing3-phthalimido-3(4-ethoxyphenyl)propionic acid there is obtained 1.3 g(88%) of crude product. Recrystallization of the crude material fromethyl acetate afforded 0.28 g (20%) of3-phthalimido-3-(4-ethoxyphenyl)propionamide as a white powder: mp190.6°-191.2° C.; 1H NMR (DMSO-d₆, 250 MHz) δ 7.75-7.95 (m, 4 H), 7.54(br s, 1 H), 7.33 (d, 2 H, J=8.6 Hz), 6.75-6.98 (m, 3 H), 5.69 (t, 1 H,J=8 Hz), 3.98 (q, 2 H, J=7 Hz), 3.19 (d, 2 H, J=8 Hz), 1.30 (t, 3 H, J=7Hz); 13C NMR (DMSO-d₆, 250 Mhz) δ 167.6, 154.1, 154.2, 130.9, 127.6,124.7, 119.5, 110.6, 59.4, 46.3, 33.3, 11.0; Anal. Calcd. for C₁₉ H₁₈ N₂O₄ 0.37 H₂ O. Theoretical: C, 66.14; H, 5.26; N, 8.12. Found: C, 66.14;H, 5.26; N, 7.81.

EXAMPLE 58

A stirred mixture 3-amino-3-phenylpropionic acid andcis-1,2-cyclohexanedicarboxylic anhydride in 10 mL of acetic acid undernitrogen was heated to reflux for 4 h and then allowed to cool to roomtemperature. The resulting mixture was concentrated to an orange yellowoil. This oil was crystallized from a 1/1 mixture of ethylacetate/hexane to afford 1.77 g (58%) of3-(cis-hexahydrophthalimido)-3-phenylpropionic acid as white crystals: ¹H NMR (DMSO-d₆) δ 12.45 (br s, 1 H, COOH), 7.33 (m, 5 H, Ph), 5.48 (dd,1 H, J=6.3, 9.6, CH), 3.41 (dd, 1 H, J=16.5, 9.6 Hz), 3.14 (dd, 1H,J=16.5, 6.3 Hz), 2.50 (m, 2 H), 1.8-1.1 (m, 8 H); ¹³ C NMR (DMSO-d₆) δ179.3, 179.2, 171.7, 138.7, 128.4, 127.5, 126.8, 50.1, 38.7, 38.6, 35.2,23.0, 22.9, 21.1. Anal. Calcd for C₁₇ H₁₉ NO₄. Theory: C, 67.76; H,6.36; N, 4.65. Found: C, 67.52; H, 6.20; N, 4.60.

EXAMPLE 59

A mixture of 3-(cis-hexahydrophthalimido)-3-phenylpropionic acid (0.903g, 3.00 mmol) and carbonyldiimidazole (0.525 g, 3.75 mmol) in 13 mL ofanhydrous tetrahydrofuran under nitrogen was stirred for 1 hour, then0.25 mL of concentrated ammonium hydroxide was added to the reactionsolution. After 20 minutes, the reaction mixture was concentrated invacuo to an oil. The oil was diluted with 20 mL of water and the mixtureextracted with ethyl acetate (20 mL). The organic layer was dried(sodium sulfate) and concentrated to afford an oil. The oil was thenpurified by flash chromatography (silica gel, 5/95 methanol/methylenechloride, R_(f) =0.3) to afford 210 mg of3-(cis-hexahydrophthalimido)-3-phenylpropionamide as an oil which slowlycrystallized to an ivory solid: ¹ H NMR (DMSO-d₆) d7.49 (s, 1 H, NH),7.4-7.2 (m, 5 H, Ar), 6.90 (s, 1 H, NH), 5.54 (t, 1 H, J=7.8 Hz, CH),3.09 (d, 2 H, J=7.8 Hz, CH2), 2.95-2.80 (m, 2 H, CH2), 1.8-1.1 (m, 8 H);¹³ C NMR (DMSO-d₆) δ 179.6, 179.5, 171.5, 139.5, 128.6, 127.7, 127.2,55.2, 50.6, 38.8, 36.5, 23.4, 23.3,21.5.

EXAMPLE 60

A stirred mixture of 4-methylphthalic acid anhydride (1.62 g, 10.0 mmol)and 3-amino-3-phenylpropionic acid (1.65 g, 10.0 mmol) in 15 mL ofacetic acid under nitrogen was heated to reflux for 6 hours. Theresulting reaction solution was concentrated in vacuo to an oil whichwas crystallized from 20 mL of a 1/1 mixture of ethyl acetate/hexane toafford 1.69 g (55%) of 3-(4-methylphthalimido)-3-phenylpropionic acid asan off-white powder: ¹ H NMR (DMSO-d₆) δ 12.5 (br s, 1 H, COOH),7.85-7.55 (m, 3 H, Ar),7.55-7.2 (m, 5H, Ar), 5.68 (dd, 1 H, J=9, 7 Hz,CH), 3.51 (dd, 1 H, J=9, 16.5 Hz), 3.29 (dd, 1 H, J=9, 16.5 Hz), 2.47(s, 3 H, CH3). Anal. Calcd for C₁₈ H₁₅ N₁ O₄. Theory; C, 69.89, H, 4.89,N, 4.53. Found: C, 69.45, H, 4.93, N, 4.55. HPLC: 95%.

EXAMPLE 61

A stirred mixture of cis-5-norbonene-endo-2,3-dicarboxylic anhydride(1.64 g, 10.0 mmol) and 3-amino-3-phenylpropionic acid (1.65 g, 10.0mmol) in 15 mL of acetic acid under nitrogen was heated to reflux for 6hours. The resulting reaction solution was concentrated in vacuo to anoil which was crystallized from a 1/1 mixture of ethyl acetate/hexane toafford 2.03 g (65%) of 3-(cis-5-norbonene-endo-2,3-dicarboxylicimide)-3-phenylpropionic acid as a white powder: ¹ H NMR (DMSO-d₆) δ12.41 (br s, 1 H, COOH), 7.29 (m, 5 H, Ph), 6.0-5.7 (m, 2 H), 5.37 (t, 1H, J=7.7 Hz), 3.5-3.1 (m, 6 H), 1.49 (m, 2 H); ¹³ C NMR (DMSO-d₆) δ177.2, 177.1, 171.4, 138.3, 134.3, 134.0, 128.1, 127.5, 127.1, 51.4,50.1, 44.8, 44.5, 44.4, 35.1. Anal. Calcd for C₈ H₁₇ NO₄. Theory: C,69.44; H, 5.50; N, 4.50. Found: C, 69.10; H, 5.33; N, 4.43.

EXAMPLE 62

A stirred mixture of 2,3,4,5-tetrachlorophthalic acid anhydride (2.85 g,10.0 mmol) and 3-amino-3-(4-methoxyphenyl)propionic acid (1.95 g, 10.0mmol) in 25 mL of acetic acid under nitrogen was heated to reflux for4.5 hours. A solid formed as the reaction mixture cooled. The resultingslurry was filtered and the solid dried in vacuo (60° C., <2 mm) toafford 4.24 g (92%) of3-(2,3,4,5-tetrachlorophthalimido)-3-(4-methoxyphenyl)propionic acid asan off-white solid contaminated with ˜1% acetic acid: mp 235.6°-238° C.;¹ H NMR (DMSO-d₆) δ 12.44 (br s, 1H, COOH), 7.36 (d, J=8.7 Hz, 2 H),6.90 (d, 1 H, J=8.7 Hz), 5.64 (m, 1 H), 3.72 (s, 3 H), 3.35 (m, 2 H); ¹³C NMR (DMSO-d₆) δ 171.5, 163.0, 158.8, 138.4, 129.9, 128.6, 128.2,127.6, .113.8, 55.0, 50.2, 35.6. Anal. Calcd for C₁₈ H₁₁ NO₅ Cl₄.Theory: C, 46.68; H, 2.39; N, 3.02. Found: C, 46.58; H 2.31; N, 2.91.

EXAMPLE 63

A stirred mixture of 4-nitrophthalic acid anhydride (1.93 g, 10.0 mmol)and 3-amino-3-(4-methoxyphenyl)propionic acid (1.95 g, 10.0 mmol) in 20mL of acetic acid under nitrogen was heated to reflux for 4.5 hours. Thereaction mixture was concentrated to an oil which was stirred in 18 mLof ethyl acetate overnight. The resulting slurry was filtered and thesolid air-dried and then dried in vacuo (70° C., <2 mm, 2 h) to afford2.52 g (68%) of the product as a pale yellow powder contaminated withacetic acid and ethyl acetate. The material was dried in vacuo overnightat 90° C. to afford a yellow glass which was slurried in 15 mL of ethylacetate to afford after filtration and drying 1.72 g (46%) of3-(4-nitrophthalimido)-3-(4-methoxyphenyl)propionic acid as a paleyellow powder contaminated with ethyl acetate: mp 90°-91.5° C.; ¹ H NMR(DMSO-d₆) δ 8.75-8.60 (m, 1 H), 8.5 (m, 2 H), 8.12 (d, J=8 Hz, 1 H),7.38 (d, 2 H, J=8.7 Hz H, Ar), 6.90 (d, 2 H, J=8.7 Hz, Ar), 5.75-5.6 (m,1 H, CHCO), 3.72 (s, 3 H, OMe), 3.47 (dd, 1 H, J=8, 16.6 Hz), 3.33 (dd,1 h, J3=7 Hz, 16.6 Hz); ¹³ C NMR (DMSO-d₆) δ 171.6, 165.9, 165.7, 158.8,151.5, 135.6, 132.4, 130.3, 129.8, 128.5, 124.7, 118.0, 113.9, 55.0,50.2, 35.8. Anal. Calcd for C₁₈ H₁₄ N₂ O₇ -1/3 EtOAc. Theory: C, 58.09;H, 4.20; N, 7.01. Found: C, 57.89; H, 4.29; N, 6.83.

EXAMPLE 64

The procedure of Example 48 was followed utilizing3-amino-3-(2-naphthyl)propionic acid and N-carbethoxyphthalimide. Thereis obtained 1.43 g (83%) of crude product as an off-white powder. Thecrude product was purified by flash chromatography (silica gel, 4-4.5%methanolmethylene chloride) to afford 1.11 g of product as a white foam.The foam was slurried in 15 mL of ethanol to afford 1.03 g of3-phthalimido-3-(2-naphthyl)propionic acid as a white powdercontaminated with ethanol and methylene chloride: ¹ H NMR (DMSO-d₆) d);12.56 (br s, 1H), 8.1-7.75 (m, 8H), 7.7-7.45 (m, 3 H), 5.89 (m, 1 H),3.62 (dd, 1 H, J3=16.6, 9 Hz), 3.46 (dd, J=16.6, 6.8 Hz); ¹³ C NMR(DMSO-d₆) δ 171.8, 167.7, 136.3, 134.6, 132.6, 132.2, 131.1, 128.3,127.9, 127.3, 126.3, 126.2, 125.6, 125.1, 123.2, 50.2, 35.8.

EXAMPLE 65

The procedure of Example 34 was followed utilizing3-phthalimido-3-(2-naphthyl)propionic acid and carbonyldiimidazole. Thecrude product is obtained as a white powder.3-Phthalimido-3-(2-naphthyl)propionamide was recrystallized from 40 mLof ethyl acetate to afford 0.259 g (35%) of the product as fine whiteprisms: ¹ H NMR (DMSO-d₆) δ 8.15-7.75 (m, 8 H, Ar), 7.75-7.4 (m, 4 h, Arand CONH), 6.94 (br s, 1 H, CONH), 5.93 (overlapping dd, 1 H, CHN),3.55-3.15 (m, 2 H, CH₂ CO); ¹³ C NMR (DMSO-d₆) δ 171.2, 167.7,136.7,134.5, 132.6, 132.2, 131.2, 128.1, 127.8, 127.3, 126.3, 126.1,125.5, 125.2, 123.1, 50.4, 36.7. Anal. Calcd for C₂₁ H₁₆ N₂ O₃. Theory:C, 73.24; H, 4.68; N, 8.13. Found: C, 73.07; H, 4.61; N, 7.91.

EXAMPLE 66

A stirred suspension of 3-amino-3-(3,4-dimethoxyphenyl)propionic acidhydrochloride (0.689 g, 2.50 mmol) and 4-pyridyldicarboxylic acidanhydride (0.373 g, 2.50 mmol) in 20 mL of acetic acid was refluxed forovernight. The cooled reaction was filtered to remove a trace amount ofsolid and the filtrate concentrated to a thick yellow oil. The oil wasdiluted with 20 mL of ethyl acetate and heated to reflux and allowed tocool to room temperature. The resulting slurry was filtered and thefiltrate concentrated to afford a yellow oil which was purified by flashchromatography (silica gel, 2/8 ethyl acetate/methylene chloride) toafford 0.592 g (64%) of methyl3-(1,3-dioxo-5-azaisoindol-2-yl)-3-(3,4-dimethoxyphenyl)-propionate as ayellow oil which slowly solidified to afford a very pale yellow solid: ¹H NMR (DMSO-d₆) δ 8.15-7.75 (m, 8 H, Ar), 7.75-7.4 (m, 4 h, Ar andCONH), 9.13 (s, 1 H, Ar), 9.11 (d, 1 H, J=4.8 Hz), 7.90 (d, 1 H, J=4.8Hz), 7.03 (s, 1 H), 6.93 (m, 2 H), 5.67 (overlapping dd, 1 H), 3.74 (s,3 H), 3.73 (s, 3 H), 3.56 (s, 3 H), 3.65-3.30 (m, 2 H); ¹³ C NMR(DMSO-d₆) δ 170.7, 166.9, 166.5, 156.0, 148.6, 148.5, 144.1, 138.7,130.4, 125.2, 119.1, 116.9, 111.6, 111.1, 55.4, 51.6, 50.1,35.4.

EXAMPLE 67

To a stirred solution of3-amino-3-(4-benzyloxy-3-methoxyphenyl)propionic acid (1.505 g, 5.00mmol) and sodium carbonate (0.572 g, 5.40 mmol) in a mixture of 75 mL ofwater and 175 mL of acetonitrile (mixture was warmed gently to dissolvesolid) was added N-carbethoxyphthalimide (1.096 g, 5.00 mmol). Themixture was stirred for 1 hour, then partially concentrated in vacuo toremove the acetonitrile. A small amount of solid formed which wasremoved by filtration. The pH of the solution was adjusted to 1 with 4NHydrochloric acid, a gum formed. To the stirred mixture was added 1 mLof ether and the mixture was then stirred overnight. The resultingslurry was filtered and the solid dried to afford 1.63 g (75%) of3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionic acid as a whitepowder; ¹ H NMR (DMSO-d₆) δ 12.43 (br s, 1 H, COOH), 8.0-7.8 (m, 4 H,Ar), 7.60-7.25 (m, 5 H), 7.15-6.85 (m, 3 H, Ar), 5.25 (dd, 1 H, J=9, 6.6Hz), 5.05 (s, 2 H, OCH2), 3.76 (s, 3 H, OMe), 3.52 (dd, 1 H, J=9, 16.5Hz), 2.29 (dd, 1 H, J=6.6, 16.5 Hz); ¹³ C NMR (DMSO-d₆) δ 171.7,167.6,148.9, 147.3, 137.0, 134.6, 131.7, 131.0, 128.3, 127.7, 127.6,123.1, 119.1, 113.3, 111.3, 69.8, 55.5, 50.1, 36.0. Anal. Calcd for C₂₅H₂₁ N₁ O₆. Theory: C, 69.66; H, 4.91; N, 3.25. Found: C, 69.50; H, 4.85;N, 3.22.

EXAMPLE 68

A mixture of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionic acid(1.00 g, 2.32 mmol), carbonyldiimidazole (0.406 g, 2.50 mmol) and acatalytic amount of dimethylaminopyridine in 20 mL of drytetrahydrofuran under nitrogen was stirred for 1 hour. To the reactionsolution was then added 0.25 mL of concentrated amrnonium hydroxide.After 15 minutes, the reaction mixture was concentrated in vacuo to anoil which was diluted with 20 mL of water and stirred overnight. Theresulting slurry was filtered and the solid dried to afford 0.645 g(65%) of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionamide as awhite powder: ¹ H NMR (DMSO-d₆) δ 7.84 (m, 4 H, Ar), 7.60-7.25 (m, 5 H),7.53 (br s, 1 H, CONH), 7.15-6.8 (m, 4 H), 5.67 (t, 1 H, J=7.8 Hz), 5.04(s, 2 H, OCH2), 3.75 (s, 3 H, OMe), 3.19 (d, 2 H, J=9, 16.5 Hz); ¹³ CNMR (DMSO-d₆) δ 171.1, 167.6,148.8, 147.2, 137.0, 134.5, 132.0, 131.2,128.3, 127.7, 127.6, 123.0, 119.3, 113.2, 111.4, 69.8, 55.5, 50.3, 36.9.Anal. Calcd for C₂₅ H₂₂ N₂ O₅. Theory: C, 69.76; H, 5.15; N, 6.51.Found: C, 69.54; H, 5.13; N, 6.28.

EXAMPLE 69

To a stirred solution of 3-amino-3-(4-butoxy-3-methoxyphenyl)propionicacid (1.31 g, 4.98 mmol) and sodium carbonate (0.554 g, 5.23 mmol) in amixture of 100 mL of water and 100 mL of acetonitrile (mixture waswarmed gently to dissolve solid, small amount of brown solid did notdissolve removed by filtration) was added N-carbethoxyphthalimide (1.09g, 4.98 mmol). The mixture was stirred for 1 hour, then partiallyconcentrated in vacuo to remove the acetonitrile. The pH was adjusted to0-1 with 4N Hydrochloric acid. An oil formed, 3 mL of ether was addedand the mixture stirred overnight. The oil did not solidify and wasextracted in methylene chloride. The organic layer was dried (sodiumsulfate) and concentrated to a yellow oil which was purified by flashchromatography (silica gel, 5/95 methanol/methylene chloride) to afford1.02 g of 3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionic acidcontaining an unidentified impurity as a yellow oil which slowlycrystallized: ¹ H NMR (DMSO-d₆) δ 7.95-7.8 (m, 4 H, Ar), 7.03 (s, 1 H),6.9 (m, 2 H), 5.61 (dd, 1 H, J=9, 6.7 Hz), 3.91 (t, 2 H, J=6.4 Hz), 3.74(s, 3 H), 3.47 (dd, 1 H, J=16.5, 6.7 Hz), 3.27 (dd, 1 H, J3=16.5, 6.7Hz), 1.75-1.55 (m, 2 H) 1.5-1.3 (m, 2 H), 0.91 (t, 3 H, J=7.3 Hz); ¹³ CNMR (DMSO-d₆) δ 171.8, 167.7, 148.8, 147.8, 134.6, 131.3, 131.1, 123.2,119.3, 112.9, 111.4, 67.8, 55.5, 50.1, 30.8, 18.7, 13.6.

EXAMPLE 70

By following the procedure of Example 65 utilizing3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionic acid andcarbonyldiimidazole, there is obtained 0.742 g (74%) of crude product asa pale yellow powder. The crude product was recrystallized from ethylacetate (16 mL) to afford 0.517 (52%) of3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionamide as fine fluffywhite needles: HPLC 99.1%; ¹ H NMR (DMSO-d₆) δ 7.95-7.75 (m, 4 H, Ar),7.54 (br s, 1 H, CONH), 7.04 (s, 1 H, Ar), 7.0-6.75 (m, 2 H), 6.86 (brs, 1 H, CONH), 5.67 (t, 1 H, J=8 Hz), 3.90 (t, 2 H, J=6 Hz), 3.73 (s, 3H), 3.20 (d, 1 H, J=8 Hz, CH₂ CO), 1.8-1.55 (m, 2 H) 1.5-1.3 (m, 2 H)0.91 (t, 3 H, J=7 Hz); ¹³ C NMR (DMSO-d₆) δ 171.2, 167.6, 148.8, 147.7,134.5, 131.6, 131.2, 123.0, 119.4, 112.8, 111.4, 67.8, 55.5, 50.3, 36.9,30.7, 18.6, 13.6.

EXAMPLE 71

A stirred mixture of tetrachlorophthalic anhydride (2.85 g, 10.0 mmol)and phenylglycine (10.0 mmol) in 20 mL of acetic acid under nitrogen washeated to reflux for 4 hours. The reaction solution was allowed to coolto room temperature with stirring. The resulting slurry was filtered andthe solid dried to afford 3.58 g (85%) ofα-(3,4,5,6-tetrachlorophthalimidio)phenylacetic acid as a white powder:¹ H NMR (DMSO-d₆) δ 7.55-7.25 (m, 5 H, Ph), 6.06 (s, 1 H, CH); ¹³ C NMR(DMSO-d₆) δ 168.4, 162.5, 138.8, 134.2, 129.4, 128.6, 128.1, 128.1,127.6, 55.7. Anal. Calcd for C₁₆ H₇ N_(1O4) Cl₄. Theory: C, 45.68; H,1.68; N, 3.34. Found: C, 45.78; H, 1.61; N, 3.29.

EXAMPLE 72

A mixture of 4,5-dichlorophthalic anhydride (2.17 g, 10.0 mmol) andD,L-phenylglycine (Aldrich, 95%) (1.59 g, 10.0 mmol) in 20 mL of aceticacid was refluxed for 6 h under nitrogen. The reaction mixture wasallowed to cool. The slurry was filtered and the solid was dried toafford 2.86 g (82%) of α-(4,5-dichlorophthalimido)phenylacetic acid as awhite powder: mp 228°-232° C.; ¹ H NMR (DMSO-d₆, 250 MHz) d: 8.25 (s, 8H), 7.52-7.30 (m, 5 H), 6.04 (s, 1H); ¹³ C NMR (DMSO-d₆) δ 168.7, 165.2,138.0, 134.6, 130.9, 129.3, 128.1, 128.1, 125.8, 55.5. Anal. Calcd forC₁₆ H₉ NO₄ Cl₂. Theoretical: C, 54.88; H, 2.59; N, 4.00. Found: C,54.93; H, 2.54; N, 3.95.

EXAMPLE 73

A slurry of 3-nitrophthalic anhydride (1.93 g, 10.0 mmol) andD,L-phenylglycine (Aldrich, 95%) (1.59 g, 10.0 mmol) in 20 mL of aceticacid was refluxed for 5 h under nitrogen. The mixture was cooled, theslurry filtered and the solid dried to afford 2.32 g (72%) ofα-(3-nitrophthalimido)phenylacetic acid as a white powder. mp 213°-229°C.; ¹ H NMR (DMSO-d₆, 250 MHz) δ 8.40-8.02 (m, 3H), 7.55-7.26 (m, 5 H),6.08 (s, 1H); ¹³ C NMR (DMSO-d₆) δ 168.6, 165.1,162.4, 144.5, 136.8,134.4, 132.8, 129.4, 129.0, 128.1,128.1,127.5, 122.5, 55.6. Anal. Calcdfor C₁₆ H₁₀ N₂ O₄. Theoretical: C, 65.31; H, 3.43; N, 9.52. Found: C,58.89; H, 3.11; N, 8.52.

EXAMPLE 74

A mixture of 3-nitrophthalic anhydride (1.54, 8.0 mmol) and3-amino-3-(4-methoxyphenyl)propionic acid (1.56 g, 8.0 mmol) in 15 mL ofacetic acid was refluxed for 3.5 h under nitrogen. The reaction wascooled and removed some of the solvent. The slurry was filtered and thesolid was dried to afford 2.34g (79%) of3-(4-methoxyphenyl)-3-(3-nitrophthalimido)propionic acid as a whitepowder: mp 178°-180° C.; ¹ H NMR (DMSO-d₆, 250 MHz) δ 8.07-8.02 (m, 3H), 7.38 (d, 2 H, J=8.7), 6.90 (d, 2 H, J=8.7, 5.68-5.07 (m, 1H), 3.72(s, 3H), 3.48-3.22 (m, 2H); ¹³ C NMR (DMSO-d₆) δ 171.6, 165.7, 163.0,158.8, 144.4, 136.4, 133.0, 130.2, 128.6, 128.5, 127.0, 122.4, 113.9,55.1, 50.0, 35.8. Anal. Calcd for C₁₈ H₁₄ N₂ O₇. Theoretical: C, 58.38;H, 1,3.81; N, 7.56. Found: C, 58.18; H, 3.79; N, 7.36.

EXAMPLE 75

A mixture of 4.5-dichlorophthalic anhydride (0.91, 4.19 mmol) and3-amino-3-(4-methoxyphenyl)propionic acid in 10 mL acetic acid wasstirred under nitrogen for 6 hours. The reaction was cooled and removedsome of the solvent. The slurry was filtered and the solid was dried toafford 1.20 g (61%) of3-(4,5-dichlorophthalimido)-3-(4-methoxyphenyl)propionic acid as a whitepowder. mp 182°-185° C.; ¹ H NMR (DMSO-d₆, 250 MHz) δ 8.19(s, 2H), 7.34(d, 2 H, J=8.7), 6.90 (d, 2H, J=8.7), 5.61(t, 1H, J=7.8), 3.72 (s, 3H),3.50-3.20 (m, 2H). ¹³ C NMR (DMSO-d₆) δ 171.6, 165.8, 158.8, 137.6,131.0, 130.4, 128.4, 125.4, 113.9, 55.1, 50.0, 35.8. Anal. Calcd for C₁₈H₁₄ N₂ O₇. Theoretical: pending

EXAMPLE 76

A mixture of 3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid (0.86g, 2.41 mmol) and carbonyldiimidazole (0.43 g, 2.65 mmol) with traceamount of 4-dimethylaminopyridine in 10 mL of tetrahydrofuran undernitrogen was stirred for 30 in at room temperature, then 0.23 mL (2.41mmol) of 3-pyridylcarbinol was added to the above solution. After 1hour, the reaction mixture was concentrated to an oil. The oil wasdissolved in 25 mL of ethylacetate and the mixture was extracted withwater (3×25 mL). The organic layer was dried over sodium sulfate and toafford the crude product as a light yellow. The crude product was thenpurified by flash chromatography (silica gel, methanol/methylenechloride, 0-2%, (v/v)) to afford 0.54 g (50%) of 3-pyridinemethyl3-phthalimido-3-(3,4-dimethoxyphenyl)propionate as a light yellow foam:¹ H NMR (DMSO-d₆, 250 MHz) δ 8.4-8.5 (m, 2 2 H), 7.84 (s, 4 H, Ar),7.5-7.6 (m, 1 H), 7.2-7.3 (m, 1 H), 6.7-7.1 (m, 3 H, Ar), 5.65 (dd, 1 H,J₁ =6 Hz, J₂ =9.6 Hz), 5.09 (s, 2 H), 3.74 (s, 6 H), 3.4-3.7 (m, 2 H);¹³ C NMR (DMSO-d₆) δ 170.1, 167.6, 149.2, 148.6, 148.4, 135.7, 134.7,131.4, 131.0, 130.8, 123.3, 123.2, 119.3, 111.7, 111.0, 63.4, 55.5,55.4, 49.9, 35.9. Anal. Calcd for C₂₅ H₂₂ N₂ O₆. Theoretical C, 67.26;H, 4.97; N, 6.27. Found C, 67.06; H, 4.99; N, 6.20.

EXAMPLE 77

A mixture of 3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid (0.60g, 1.69 mmol), carbonyldiimidazole (0.28 g, 1.77 mmol) and a traceamount of 4-dimethylaminopyridine in 10 mL of tetrahydrofuiran wasstirred at room temperature under nitrogen for 30 min. To the reactionmixture was added 3-amihomethylpyridine (0.18 mL, 1.77 mmol). Thereaction mixture was stirred for 20 min, then 10 mL of water was addedand the tetrahydrofuiran was removed under reduced pressure. Theresulting slurry was filtered, the solid was washed with water, anddried in vacuro (60° C., <1 mm) to afford 0.57 g (76%) ofN-3-methylpyridyl 3-phthalimido-3-(3,4-dimethoxyphenyl)propionamde as awhite powder: mp 171.2°-172.4° C.; ¹ H NMR (DMSO-d₆, 250 MHz) δ 8.69 (t,1 H, J=6 Hz), 8.36 (m, 2H), 7.85 (s, 4 H, Ar), 6.8-7.4 (m, 5 H), 5.71(t, 1 H, J=8 Hz), 4.22 (d, 2 H, J=5.2 Hz), 3.73 (s, 3 H), 3.71 (s, 3 H),3.31 (d, 2 H, J=8 Hz); ¹³ C NMR (DMSO-d₆) δ 169.4, 167.7, 148.5, 148.3,147.9, 134.7, 134.6, 134.5, 131.4, 131.2, 123.1, 119.5, 111.6, 111.2,55.5, 55.4, 50.6, 39.6, 37.4. Anal. Calcd for C₂₅ H₂₃ N₃ O₅. TheoreticalC, 67.41; H, 5.20; N, 9.43. Found C, 67 35; H, 5.14; N, 9.34.

EXAMPLE 78

To a stirred solution of 3-phthalimido-3-(3,4-dichlorophenyl)propionicacid (1.10 g, 3.02 mmol) in 20 mL of tetrahydrofuran at room temperatureunder nitrogen was added carbonyldiimidazole (0.51 g, 3.17 mmol) and acatalytic amount of 4-dimethylaminopyridine. The mixture was stirred for45 in and then concentrated ammonium hydroxide (0.21 mL, 3.2 mmol) wasadded. The reaction mixture was stirred for 10 minutes and then thetetrahydrofuran was removed under reduced pressure. To the resultingmixture was added 20 mL of water, a light yellow oil was formed. To themixture was added 3 mL of ether, the mixture was stirred at roomtemperature for 1 hour. The resulting slurry was filtered, the solid waswashed with water and air-dried to afford 0.73 g of the crude product asa white solid. The crude product was purified by flash chromatography(silica gel hexane/methylene chloride, 22-0% (v/v)) to afford 0.39 g(36%) of 3-phthalimido-3-(3,4-dichlorophenyl)propionamide as a whitepowder: ¹ H NMR (DMSO-d₆, 250 MHz) δ 7.83 (m, 4 H, Ar), 7.35-7.75 (m, 4H), 6.93 (br s, 1 H), 5.72 (t, 1 H, J=8 Hz), 3.25 (dd, 1 H, J₁ =8 Hz, J₂=15 Hz), 3.14 (dd, 1 H, J₁ =8 Hz, J₂ =15 Hz); ¹³ C NMR (DMSO-d₆) δ170.8, 167.6, 140.2, 134.6, 131.2, 131.0, 130.7, 130.3, 129.2, 127.7,123.2, 49.3, 36.5. Anal. Calcd for C₁₇ H₁₂ N₂ O₃ Cl₂. Theoretical C,54.69; H, 3.54; N, 7.53. Found C, 54.69; H, 3.38; N, 7.15.

EXAMPLE 79

To 150 mL of stirred methanol at 0° C. under nitrogen was slowly addedthionyl chloride (14.2 mL, 194.4 mmol). To the reaction mixture was thenadded 3-amino-3-(3,4-dimethoxyphenyl)propionic acid (15.5 g, 64.8 mmol).The reaction mixture was stirred at 0° C. for 30 minutes and thenallowed to warm to room temperature, and stirred overnight. The reactionsolution was concentrated to an oil and then diluted with 200 mL of CH₃OH/Et₂ O (1/3) and stirred. The resulting slurry was filtered and thesolid was washed with a copious amount of ether. The solid was dried invacuo (60° C., <1 mm) to afford 1.83 g (66%) of methyl3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride as a whitepowder: ¹ H NMR (DMSO-d₆, 250 MHz) δ 8.59 (br s, 3 H, NH₃), 6.9-7.3 (m,3 H, Ar), 4.52 (overlapping dd, 1 H), 3.77 (s, 3 H, OCH₃), 3.75 (s, 3 H,OCH₃), 3.57 (s, 3 H, OCH₃), 3.16 (dd, 1 H, J₁ =6 Hz, J₂ =16 Hz), 2.98(dd, 1 H, J₁ =8 Hz, J₂ =16 Hz), ¹³ C NMR (DMSO-d₆) δ 169.6, 149.0,129.0, 120.0, 111.5, 111.4, 55.7, 55.5, 51.7, 50.8, 38.5. Anal. Calcdfor C₁₂ H₁₈ NO₄ Cl. Theoretical C, 52.27; H, 6.58; N, 5.08. Found C,52.44; H, 6.53; N, 5.01.

EXAMPLE 80

A mixture of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionatehydrochloride (1.38 g, 5.00 mmol), sodium carbonate (0.53 g, 5.00 mmol),and N-carbethoxyphthalimide (1.10 g, 5.0 mmol) in 40 mL ofacetonitrile/water (1/1) was stirred for 1 hour at room temperature. Thereaction solution was then partially concentrated under reduced pressureto remove the acetonitrile. This afforded a white gum in water. To themixture was then added 5 mL of ether and the mixture was stirred for 2hours. The resulting slurry was filtered, the solid was washed with acopious amount of water and air-dried overnight to afford 1.69 g (92%)of methyl 3-phthalimido-3-(3,4-dimethoxyphenyl)propionate as a whitesolid: mp 114.1°-115.6° C.; ¹ H NMR (DMSO-d₆, 250 MHz)d 7.80-7.95 (m, 4H, Ar), 6.80-7.10 (m, 3 H, Ar), 5.65 (dd, 1 H, J₁ =7 Hz, J₂ =9 Hz), 3.74(s, 3 H, OCH₃), 3.72 (s, 3 H, OCH₃), 3.55 (s, 3 H, OCH₃), 3.30-3.67 (m,2 H); ¹³ C NMR d(DMSO-d₆)d 170.8, 167.6, 148.6, 148.4, 134.7, 131.1,131.0, 123.2, 119.3, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal. Calcdfor C₂₀ H₁₉ NO₆. Theoretical C, 65.03; H, 5.18; N, 3.79. Found C, 65.17;H, 5.14; N, 3.75. HPLC 99%.

EXAMPLE 81

To a stirred solution of benzaldehyde (1.58 mL, 15.5 mmol) in 10 mL ofabsolute ethanol at room temperature under nitrogen was added(R)-α-methylbenzylamine (2.0 mL, 15.51 mmol, 99% ee.). The reactionmixture was stirred for 3 hours. The reaction solution was then driedover magnesium sulfate and diluted to a 60 mL volume with EtOH. Ethanolwashed Raney nickel Ni (˜1.5 g) was added and the resulting suspensionwas treated with 58 psi of hydrogen in a Parr Type Shaker. After 1 day,additional Raney nickel (˜1 g) and 30 mL of ethanol were added and thehydrogenolysis continued for 3 days. The reaction mixture was filteredthrough Celite to remove the catalyst and concentrated to afford 3.11 g(95%) of N-benzyl (R)-α-methylbenzylamine as a pale yellow oilcontaminated with ˜5% of benzyl alcohol and (R)-α-methylbenzylamine; ¹ HNMR (DMSO-d₆, 250 MHz) δ 7.1-7.5 (m, 10 H, Ar), 3.68 (q, 1 H, J=6.6 Hz),3.48 (dd, 2 H, J₁ =13.6 Hz, J₂ =20.5 Hz), 1.26 (d, 3 H, J=6.6 Hz, CH₃);¹³ C NMR (DMSO-d₆) δ 146.1, 141.0, 128.2, 128.0, 127.8, 126.5, 126.4,56.7, 50.6, 24.5. This mixture was used directly in the next reaction.

EXAMPLE 82

To stirred solution of N-benzyl (R)-α-methylbenzylamine (1.9 g, 9.0mmol) in 50 mL of tetrahydrofuran at 0° C. under nitrogen was addedn-butyl lithium (1.6M in hexanes; 9.0 mmol). The resulting red solutionwas stirred at 0° C. for 15 min and then cooled to -78° C. To thereaction mixture was then dropwise added methyltrans-3-(3,4-dimethoxyphenyl)propion-2-enate (1.33 g, 6.0 mmol) in 20 mLtetrahydrofuran and the mixture was stirred for 15 in at -78° C. toafford a yellow solution. The reaction was then quenched by the additionof saturated ammonium chloride (20 mL). The mixture was allowed to warmto room temperature and poured into 40 mL of saturated sodium chloride(aq). The mixture was extracted with ether (2×60 mL) and the combinedorganic layers dried (MgSO₄) and concentrated to afford 3.35 g of crudeproduct as a yellow oil. The oil was purified by flash chromatography(silica gel, hexane/methylene chloride, 30-0%, (v/v)) to afford 1.24 g(48%) of methyl(S)-N-benzyl-N-(R)-α-methylbenzyl-3-(3,4-dimethoxyphenyl)propionateadduct as colorless oil: ¹ H NMR (DMSO-d₆, 250 MHz) δ 6.7-7.5 (m, 13 H,Ar), 3.9-4.2 (m, 2 H), 3.78 (s, 3 H, OCH₃), 3.73 (s, 3 H, OCH₃), 3.65(s, 2 H), 3.43 (s, 3 H, OCH₃), 2.6-2.9 (m, 2 H), 1.03 (d, 3 H, J=7 Hz);¹³ C NMR (DMSO-d₆) δ 171.6, 148.3, 147.8, 144.6, 141.5, 133.6, 128.1,128.0, 127.7, 127.5,126.7, 126.4, 119.6, 111.9, 111.2, 58.2, 56.4, 55.4,55.3, 51.1, 49.7, 35.6, 17.1.

EXAMPLE 83

Debenzylation of the above pure adduct of Example 82 was performedfollowing the procedure S. G. Davies and O. Ichihara (TetrahedronAsymmetry 1991, 2, 183.). To a stirred solution methyl(S)-3-(N-benzyl-N-(R)-α-methylbenzylamino)-3-(3,4-dimethoxyphenyl)propionate(1.20 g, 2.77 mmol) in a mixture of methanol (20 mL), water (2 mL) andacetic acid (0.5 mL) was added 20% palladium hydroxide on charcoal. Thereaction rixture was treated with hydrogen (54 psi) at room temperaturefor 23 h on a Parr Type Shaker. The reaction mixture was filteredthrough Celite and then concentrated to afford the product as an acetatesalt. The salt was dissolved in 10 mL of water, stirred with 0.7 mL 4NHCl and then concentrated to a white solid. The solid was diluted with40 mL of ether and stirred for 20 min. The slurry was filtered and thesolid was dried in vacuo (room temperature, <1 mm) to afford 0.57 g(75%) of methyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionatehydrochloride as a white solid: HPLC 96% ee (Chiral Crown-pack CR+column); ¹ H NMR (DMSO-d₆, 250 MHz) δ 8.73 (br s, 3 H, NH₃), 6.90-7.40(m, 3 H, Ar), 4.51 (dd, 1 H, J₁ =6 Hz, J₂ =8 Hz), 3.77 (s, 3 H, OCH₃),3.75 (s, 3 H, OCH₃), 3.56 (s, 3 H, OCH₃), 3.2 (dd, 1 H, J₁ =6 Hz, J₂ =16Hz), 3.0 (dd, 1 H, J₁ =8 Hz, J₂ =16 Hz); ¹³ C NMR (DMSO-d₆) δ 169.6,149.0, 148.7, 129.0, 120.0, 111.5, 111.4, 55.7, 55.5, 51.7, 50.8, 38.6.Anal.Calcd for C₁₂ H₁₈ NO₄ Cl-0.48 H₂ O. Theoretical C, 50.67; H, 6.72;N, 4.92. Found C, 50.67; H, 6.46; N, 4.83.

EXAMPLE 84

Methyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate (0.45 g, 1.63mmol), sodium carbonate (0.17 g, 1.63 mmol) and N-carboethoxyphthalimide(0.36 g, 1.63 mmol) were allowed to react according to the procedure ofExample 85. Methyl (S)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionatewas obtained as a white powder, 0.51 g (85%); ¹ H NMR (DMSO-d₆, 250 MHz)δ 7.87 (br s, 4 H, Ar), 6.80-7.10 (m, 3 H, Ar), 5.65 (dd, 1 H, J₁ =7 Hz,J₂ =9 Hz), 3.73 (s, 3 H, OCH₃), 3.72 (s, 3 H, OCH₃), 3.55 (s, 3 H,OCH₃), 3.30-3.67 (m, 2 H); ¹³ C NMR (DMSO-d₆) δ 170.8, 167.7, 148.6,148.4, 134.7, 131.1, 131.0, 123.2, 119.3, 111.7, 111.0, 55.5, 51.6,49.9, 35.6. Anal.Calcd for C₂₀ H₁₉ NO₆. Theoretical C, 65.03; H, 5.18;N, 3.79. Found C, 64.94; H, 5.29; N, 3.86. HPLC 97%.

EXAMPLE 85

Benzaldehyde (3.94 mL, 38.8 mmol) and (S)-α-methylbenzylamine (5.0 mL,38.8 mmol, 96% ee.) were allowed to react according to the procedure ofExample 86 to yield 7.88 g (96%) of N-benzyl-(S)-α-methylbenzylamine asan oil contaminated with ˜5% of benzyl alcohol and(S)-α-methylbenzylamine: ¹ H NMR (DMSO-d₆, 250 MHz) δ 7.15-7.45 (m, 10H, Ar), 3.69 (q, 1 H, J=6.5 Hz), 3.48 (dd, 2 H, j₁ =13.6 Hz, J₂ =20.9Hz), 2.45 (br s, 1 H, NH), 1.26 (d, 3 H, J=6.5 Hz, CH₃); ¹³ C NMR(DMSO-d₆) δ 146.0, 141.0, 128.1, 128.0, 127.8, 126.4, 126.3, 56.7, 50.6,24.5. This mixture was directly used in the next reaction.

EXAMPLE 86

Butyl lithium (1.6M in hexanes; 8.44 mmol),N-benzyl-(S)-α-methylbenylamine (1.78 g, 8.44 mmol) and3-(3,4-dimethoxyphenyl)propyl-2-enate (1.50 g, 6.75 mmol) were allowedto react according to the procedure of Example 87 to yield 3.7 g of thecrude product as a yellow oil. The oil was purified by flashchromatography (silica gel, ether/hexane, 20/80) to afford 0.57 g (20%)of methyl(R)-3-(N-benzyl-N-(S)-α-methylbenzylamino)-3-(3,4-dimethoxyphenyl)propionateas a colorless oil; ¹ H NMR (DMSO-d₆, 250 MHz) δ 6.80-7.50 (m, 13 H,Ar), 4.15 (dd, 1 H, J₁ =6 Hz, J₂ =9 Hz), 4.04 (q, 1 H, J=7 Hz), 3.78 (s,3 H, OCH₃), 3.73 (s, 3 H, OCH₃), 3.69 (s, 2 H), 3.43 (s, 3 H, OCH₃),2.87 (dd, 1 H, J₁ =6Hz, J₂ =15 Hz), 2.67 (dd, 1 H, J₁ =9Hz, J₂ =15 Hz),1.04 (d, 3 H, J=7 Hz, CH₃); ¹³ C NMR (DMSO-d₆) δ 171.6, 148.4, 147.8,144.7, 141.5, 133.6, 128.1, 128.0, 127.8, 127.5,126.7, 126.4, 119.6,111.9, 111.2, 58.2, 56.4, 55.4, 55.3, 51.1, 49.7, 35.6, 17.1.

EXAMPLE 87

Debenzylation of the adduct prepared in Example 86 was performed asdescribed in Example 88. A solution of methyl(R)-3-(N-benzyl-N-(S)-α-methylbenzylamino)-3-(3,4-dimethoxyphenyl)propionate(0.57 g, 1.3 mmol) in methanol (10 mL), water (1 mL) and acetic acid(0.25 mL) in the presence of 20% palladium hydroxide on charcoal wastreated with hydrogen (59 psi) at room temperature for 23 h in a ParrType Shaker. The mixture was filtered through Celite and thenconcentrated to afford the primary amine in an acetate salt, which wasdissolved in 10 mL of water, stirred with 0.32 mL (4N) HCl andconcentrated to a white solid. To the solid was added 10 mL of ether andthe mixture stirred for 30 min. The slurry was filtered, the solid wasdried in vacuo (room temperature, <1 mm) to afford 0.32 g (90%) ofmethyl (R)-3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride as awhite powder: Chiral HPLC (Crownpak Cr+ Column 92% ee; ¹ H NMR (DMSO-d₆,250 MHz) δ 8.61 (br s, 3 H, NH₃), 6.90-7.30 (m, 3 H, Ar), 4.53 (br s, 1H), 3.77 (s, 3 H, OCH₃), 3.75 (s, 3 H, OCH₃), 3.57 (s, 3 H, OCH₃), 3.16(dd, 1 I, J₁ =6 Hz, J₂ =16 Hz), 2.98 (dd, 1 H, J₁ =8 Hz, J₂ =16 Hz); ¹³C NMR (DMSO-d₆) δ 169.5, 149.0, 148.6, 128.9, 119.8, 111.4, 111.2, 55.6,55.4, 51.7, 50.7, 38.4. Anal. Calcd for C₁₂ H₁₈ NO₄ Cl 0.48 H₂ O.Theoretical C, 50.67; H, 6.72; N, 4.92. Found C, 50.66; H, 6.54; N,4.81.

EXAMPLE 88

Methyl (3R)-3-amino-3-(3,4-dimethoxyphenyl)propionate (0.25 g, 0.91mmol), sodium carbonate (0.10 g, 0.91 mmol) and N-carboethoxyphthalimide(0.20 g, 0.91 mmol) were allowed to react according to the procedure ofExample 85. Methyl (3R)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionatewas obtained as a white powder, 0.29 g (88%); ¹ H NMR (DMSO-d₆, 250MHz)δ 7.87 (br s, 4 H, Ar), 6.80-7.10 (m, 3 H, Ar), 5.64 (dd, 1 H, J₁ =7 Hz,J₂ =9 Hz), 3.73 (s, 3 H, OCH₃), 3.72 (s, 3 H, OCH₃), 3.55 (s, 3 H),OCH₃), 3.30-3.67 (m, 2 H); ¹³ C NMR (DMSO-d₆) δ 170.8, 167.6, 148.6,148.4, 134.7, 131.1, 131.0, 123.2, 119.2, 111.7, 111.0, 55.5, 51.6,49.9, 35.6. Anal. Calcd for C₂₀ H₁₉ NO₆ 0.80 H₂ O. Theoretical C, 62.60;H, 4.99; N, 3.69. Found C, 62.60; H, 4.93; N, 3.69. HPLC 99.9%.

EXAMPLE 89

To a stirred solution of methyl3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (0.87 g,3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water(10 mL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68g, 3.0 mmol). The resulting solution was stirred for 3 hours at roomtemperature. The acetonitrile was removed in vacuo. To the resultingmixture was added ether (5 mL) and the mixture was stirred at roomtemperature overnight allowing the ether to evaporate. The resultingwhite solid was filtered. The solid was washed with water, air dried,and dried in vacuo (60° C., <1 mm) to afford 1.0 g (87%) of methyl3-phthalimido-3-(3-ethoxy-4-methoxyphenyl)propionate as a white solid:mp 86°-87° C.; ¹ H NMR (CDCl₃) δ 7.86-7.63 (m, 4 H), 7.16-7.05 (m, 2 H),6.88-6.76 (m, 1 H), 5.77 (dd, J=5.9, 10 Hz, 1 H), 4.11 (q, J=7 Hz, 2 H),3.84 (s, 3 H), 3.77 (dd, J=10, 6.7 Hz, 1 H), 3.63 (s, 3 H), 3.25 (dd,J=5.9, 16.5 Hz, 1 H), 1.45 (t, J=7 Hz, 3 H); ¹³ C NMR (CDCl₃) δ 171.0,168.0, 149.0, 148.2, 133.9, 131.7, 130.9, 123.2, 120.2, 112.5, 111.1,64.3, 55.8, 51.8, 50.7, 35.8, 14.6; HPLC (Waters Nova-Pak C₁₈ column,3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 45/55, acetonitrile/0.1% aqueousphosphoric acid 6 min. 100%, Anal. Calcd. for C₂₁ H₂₁ NO₆. Theoretical:C, 65.79; H, 5.52; N, 3.65. Found: C, 65.71; H, 5.70; N, 3.63.

EXAMPLE 90

To a stirred solution of methyl3-amino-3-(3-butoxy-4-methoxyphenyl)propionate hydrochloride (0.95 g,3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water(10 mL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68g, 3.0 mmol). The resulting solution was stirred for 3 hours at roomtemperature. The acetonitrile was removed in vacuo. To the resultingmixture was added ether (5 mL) and the mixture was stirred at roomtemperature overnight allowing the ether to evaporate. The resultingwhite solid was filtered. The solid was washed with water, air dried,and dried in vacuo (60° C., <1 mm) to afford 1.1 g (89%) of methyl3-phthalimido-3-(3-butoxy-4-methoxyphenyl)propionate as a white solid:mp 54°-55° C.; ¹ H NMR (CDCl₃) δ 7.86-7.63 (m, 4 H), 7.16-7.05 (m, 2 H),6.85-6.76 (m, 1 H), 5.76 (dd, J=5.9, 10 Hz, 1 H) 4.02 (t, J=6.7 Hz, 2H), 3.86-3.71 (m, 1 H), 3.83 (s, 3 H), 3.63 (s, 3 H), 3.24 (dd, J=5.9,16.5 Hz, 1 H), 1.89-1.73 (m, 2 H), 1.59-1.41 (m, 2 H), 1.04-0.89 (m, 3H); ¹³ C NMR (CDCl₃) δ 171.1, 168.1, 149.2, 148.5, 133.9, 131.8, 130.9,123.3, 120.2, 112.7, 111.4, 68.6, 55.9, 51.9, 50.7, 35.9, 31.1, 19.2,13.9; HPLC (Waters Nova-Pak C₁₈ column, 3.9×150 mm, 4 micron, 1 mL/min,240 nm, 55/45, acetonitrile/0.1% aqueous phosphoric acid) 6.5 min, 100%,Anal. Calcd. for C₂₃ H₂₅ NO₆. Theoretical: C, 67.14; H, 6.12; N, 3.40.Found: C, 66.89; H, 6.15; N, 3.31.

EXAMPLE 91

A solution of 3-phthalimido-3-(3,4-diisopropoxyphenyl)propionic acid(1.0 g, 2.4 mmol), 1,1 carbonyldiimidazole (0.43 g, 2.6 mmol), and4-dimethylaminopyridine (trace) in tetrahydrofuran (18 mL) was stirredfor 1.5 hours at room temperature. To the solution was added ammoniumhydroxide (0.24 mL, 3.7 mmol, 28-30%) and stirring was continued for 2hours. The tetrahydrofuran was removed in vacuo leaving an oil. To theoil was added 2 mL of water and the mixture was stirred at roomtemperature overnight. The resulting slurry was filtered, the solid waswashed with water, air dried, and dried in vacuo (60° C., <1 mm) toafford 0.87 g (88%) of3-phthalimido-3-(3,4-diisopropoxyphenyl)propionamide as a white solid:mp 153°-154.5° C.; ¹ H NMR (DMSO-d₆) δ 7.92-7.78 (m, 4H), 7.55 (s, 1H),7.03(s, 1H), 6.93-6.77 (m, 3H), 5.71-5.56 (m, 1H), 4.51-4.33 (m, 2H),3.25-3.06 (m, 2H), 1.31-1.08 (m, 12H); ¹³ C NMR (DMSO-d₆) δ 171.7,168.3, 148.9, 133.9, 132.1, 131.9, 123.3, 120.9, 117.7, 72.2, 72.1,51.5, 37.9, 22.2; Anal. Calcd. for C₂₃ H₂₆ N₂ O₅. Theoretical: C, 67.30;H, 6.38; N, 6.82. Found: C, 67.01; H, 6.35; N, 6.69.

EXAMPLE 92

A stirred suspension of 3-nitrophthalic anhydride (2.1 g, 10 mmol),sodium acetate (0.82 g, 10 mmol), and methyl3-amino-3-(3-ethoxy-4-methoxyphenyl) propionate hydrochloride (2.9 g, 10mmol) in 30 mL of acetic acid was heated to reflux under nitrogen for 12hours. The acetic acid was removed in vacuo to afford an orange gumwhich was dissolved in methylene chloride (30 mL) and was washed with asaturated aqueous solution of sodium bicarbonate (35 mL). The organiclayer was separated and the aqueous layer was extracted with methylenechloride (30 mL). The combined organic extracts were dried overmagnesium sulfate, filtered and concentrated in vacuo to afford 4.0 g(93%) of methyl 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as a yellow solid: mp 56°-57.5° C.; ¹ H NMR (CDCl₃) δ8.11-8.04 (m, 2 H), 7.94-7.83 (m, 1 H), 7.14-7.05 (m, 2 H), 6.86-6.76(m, 1 H), 5.76 (dd, J=5.6, 10.3 Hz, 1 H), 4.10 (q, J=7 Hz, 2 H), 3.84(s, 3 H), 3.91-3.74 (m, 1 H), 3.64 (s, 3 H), 3.28-3.15 (m, 1 H), 1.46(t, J=7 Hz, 3 H); ¹³ C NMR (CDCl₃) δ 170.9, 165.6, 162.6, 149.4, 148.3,145.1, 135.2, 133.8, 130:1, 128.5, 127.0, 123.4, 120.4, 112.6, 111.3,64.4, 55.9, 51.9, 51.5, 35.4, 14.7; Anal. calcd for C₂₁ H₂₀ N₂ O₈.Theoretical: C, 58.88; H, 4.71; N, 6.54. Found: C, 58.89; H, 4.69; N,6.40.

EXAMPLE 93

To a solution of methyl3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate (2.5 g,5.8 mmol) in 25 mL of ethyl acetate was added 0.25 g of 10% palladium oncarbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatusat 55-60 psi of hydrogen overnight. The reaction mixture was filteredthrough celite and the filtrate was concentrated in vacuo to afford ayellow solid. The crude product was purified by flash columnchromatography (silica gel, 7% ethyl acetate/methylene chloride). Theresulting solid was recrystallized (60 mL ethyl acetate/20 mL hexane)and was then dried in vacuo (60° C., <1 mm) to afford 1.28 g (55%) ofmethyl 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate asa yellow solid: mp 134°-136° C.; ¹ H NMR (CDCl₃) δ 7.40-7.26 (m, 1 H);7.16-7.01 (m, 3 H), 6.86-6.72 (m, 2 H), 5.71 (dd, J=6, 9.8 Hz, 1 H),5.28 (br s, 2 H), 4.10 (q, J=7 Hz, 2 H), 3.83 (s, 3 H), 3.73 (dd, J=9.8,16.5 Hz, 1 H), 3.64 (s, 3 H), 3.24 (dd, J=6, 16.5 Hz, 1 H), 1.44 (t, J=7Hz, 3 H); ¹³ C NMR (CDCl₃) δ 171.1, 169.8, 168.3, 148.9, 148.1, 145.3,134.9, 132.3, 131.3, 120.9, 120.0, 112.5, 112.4, 111.1, 110.8, 64.2,55.8, 51.8, 50.2, 36.0, 14.6; HPLC (Waters Nova-Pak C₁₈ column, 3.9×150mm, 4 micron, 1 mL/min, 240 nm, 50/50, acetonitrile/0.1% aqueousphosphoric acid) 5 min, 100%; Anal. Calcd. for C₂₁ H₂₂ N₂ O₆.Theoretical: C, 63.31, H, 5.57, N, 7.03. Found: C, 63.11; H, 5.50; N,6.99.

EXAMLE 94

A stirred suspension of 4-nitrophthalic anhydride (1.6 g, 7.0 mmol),sodium acetate (0.6 g, 7 mmol), and methyl3-amino-3-(3-ethoxy-4-methoxyphenyl) propionate hydrochloride (2 g, 7mmol) in 25 mL of acetic acid was heated to reflux under nitrogen for3.5 hours. The acetic acid was removed in vacuo to afford an orange gumwhich was dissolved in methylene chloride (20 mlL) and was washed with asaturated aqueous solution of sodium bicarbonate (10 mL). The organiclayer was separated and the aqueous layer was extracted with methylenechloride (10 mL). The combined organic extracts were dried overmagnesium sulfate, filtered and concentrated in vacuo to afford 2.8 g(93%) of methyl 3-(4-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as a yellow solid: mp 54°-61° C.; ¹ H NMR (CDCl₃) δ 8.66-8.52(m, 2 H), 8.05-7.96 (m, 1 H), 7.16-7.06 (m, 2 H), 6.89-6.77 (m, 1 H),5.76 (dd, J=5.4, 10.5 Hz, 1 H), 4.10 (q, J=7 Hz, 2 H), 3.86 (s, 3 H),3.85 (dd, J=10.5, 16.8 Hz, 1 H), 3.20 (dd, J=16.8, 5.4 Hz, 1 H), 1.46(t, J=7 Hz, 3 H); ¹³ C NMR (CDCl₃) δ 170.9, 165.9, 165.7, 151.7, 149.4,148.4, 136.2, 133.2, 130.2, 129.2, 124.5, 120.3, 118.7, 112.4, 111.3,64.4, 55.9, 52.0, 51.5, 35.5, 14.7; Anal. calcd for C₂₁ H₂₀ N₂ O₈.Theoretical: C, 58.88; H, 4.71; N, 6.54. Found: C, 58.92; H, 4.59; N,6.48.

EXAMPLE 95

To a solution of methyl3-(4-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate (2.3 g,5.4 mmol) in 25 mL of ethyl acetate was added 0.25 g of 10% palladium oncarbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatusat 55-60 psi of hydrogen overnight. The reaction mixture was filteredthrough celite and the filtrate was concentrated in vacuo to afford ayellow solid. The crude product was purified by flash columnchromatography (silica gel, 20% ethyl acetate/methylene chloride). Theresulting solid was dried in vacuo (60° C., <1 mm) to afford 1.98 g(93%) of methyl3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as ayellow solid: mp 65°-67° C.; ¹ H NMR (CDCl₃) δ 7.56-7.48 (m, 1 H);7.15-6.93 (m, 3 H), 6.85-6.71 (m, 2 H), 5.70 (dd, J=6.1, 9.7 Hz, 1 H),4.35 (br s, 2 H), 4.09 (q, J=7 Hz, 2 H), 3.83 (s, 3 H), 3.72 (dd, J=9.7,16.4 Hz, 1 H), 3.62 (s, 3 H), 3.23 (dd, J=6.1, 16.4 Hz, 1 H), 1.44 (t,J=7 Hz, 3 H); ¹³ C NMR (CDCl₃) δ 171.2, 168.3, 168.2, 152.3, 148.9,148.1, 134.6, 131.4, 125.1, 120.3, 120.2, 117.9, 112.6, 111.2, 108.4,64.3, 55.9, 51.8, 50.4, 38.1, 14.7; HPLC (Waters Radial-Pak Phenylcolumn, 1.8×100 mm, 1 mL/min, 240 nm, 55/45, acetonitrile/0.1% aqueousphosphoric acid) 3.5 min, 100%; Anal. Calcd. for C₂₁ H₂₂ N₂ O₆.0.29 H₂O. Theoretical: C, 62.49, H, 5.63, N, 6.94. Found: C, 62.53; H, 5.62; N,6.78.

EXAMPLE 96

A stirred suspension of 3-nitrophthalic anhydride (0.24 g, 1.13 mmol)and 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanenitrile (0.25 g, 1.13mmol) in 6 mL of acetic acid was heated to reflux under nitrogen for 12hours. The acetic acid was removed in vacuo to afford an orange gumwhich was dissolved in methylene chloride (10 mL) and was washed with asaturated aqueous solution of sodium bicarbonate (2×10 mL). The organiclayer was separated and the aqueous layer was extracted with methylenechloride (10 mL). The combined organic extracts were dried overmagnesium sulfate, filtered and concentrated in vacuo to afford a yellowoil. The crude product was purified by flash column chromatography(silica gel, 5% ethyl acetate/methylene chloride) and the resultingsolid was dried in vacuo (60° C., <1 mm) to afford 0.25 g (56%) of3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile as ayellow solid: mp 155.5°-157° C.; ¹ H NMR (CDCl₃) δ 8.20-8.09 (m, 2 H),8.02-7.86 (m, 1 H), 7.15-7.02 (m, 2 H), 6.88-6.76 (m, 1 H), 5.64 (dd,J=6.3, 10.6 Hz, 1 H), 4.09 (q, J=7 Hz, 2 H), 3.85 (s, 3 H), 3.84 (dd,J=10.6, 16.7 Hz, 1 H), 3.26 (dd, J=6.3, 16.7 Hz, 1 H), 1.46 (t, J=7 Hz,3 H); ¹³ C NMR (CDCl₃) δ 165.3, 162.3, 150.1, 148.7, 144.9, 135.7,133.5, 129.0, 128.1, 127.4, 123.2, 120.3, 116.6, 112.1, 111.5, 64.6,55.9, 51.9, 20.9, 14.7; Anal. calcd for C₂₀ H₁₇ N₃ O₆. Theoretical: C,60.76; H, 4.33; N, 10.63. Found: C, 60.59; H, 4.22; N, 10.65.

EXAMPLE 97

To a solution of3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile (0.2g, 0.5 mmol) in 30 mL of ethyl acetate was added 0.05 g of 10% palladiumon carbon catalyst. The mixture was hydrogenated in a Parr-Shakerapparatus at 55-60 psi of hydrogen overnight. The reaction mixture wasfiltered through celite and the filtrate was concentrated in vacuo toafford a yellow oil. The crude product was purified by flash columnchromatography (silica gel, 3% ethyl acetate/methylene chloride). Theresulting yellow solid was then dried in vacuio (60° C., <1 mm) toafford 0.09 g (50%) of3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile: mp171°-172.5° C.; ¹ H NMR (CDCl₃) δ 7.47-7.356 (m, 1 H); 7.19-7.00 (m, 3H), 6.90-6.29 (m, 2 H), 5.56 (dd, J=6.6, 10 Hz, 1 H), 5.24 (s, 2H), 4.09(q, J=7 Hz, 2 H), 3.84 (s, 3 H), 3.77 (dd, J=10, 16.8 Hz, 1 H), 3.27(dd, J=6.6, 16.8 Hz, 1 H), 1.45 (t, J=7 Hz, 3 H); ¹³ C NMR (CDCl₃) δ169.4, 167.9, 149.6, 148.5, 145.5, 135.5, 132.1, 129.4, 121.3, 120.0,117.1, 113.0, 112.2, 111.4, 110.6, 64.5, 55.9, 50.7, 21.1, 14.7; EPLC(Waters Nova-Pak C₁₈ column, 3.9×150 mm, 4 micron, 1 nL/min, 240 nm,40/60, acetonitrile/0.1% aqueous phosphoric acid) 4.5 min, 100%; Anal.Calcd. for C₂₀ H₁₉ N₃ O₄. Theoretical: C, 65.74, H, 5.24, N, 11.50.Found: C, 65.54; H, 5.23; N, 11.23.

EXAMPLE 98

To a solution of methyl3-(4-nitrophthalimido)-3-(3,4-diethoxyphenyl)propionate (1.87 g, 4.23mmol) in a mixture of ethyl acetate (30 mL) and methanol (30 mL) wasadded 0.18 g of 10% palladium on carbon catalyst. The mixture washydrogenated in a Parr Shaker apparatus at 55-60 psi of hydrogenovernight. The reaction mixture was filtered through celite and thefiltrate was concentrated in vacuo to afford 1.67 g of a yellow solid.The crude product was purified by flash column chromatography (silicagel, 35% ethyl acetate/hexane). The resulting solid was then dried invacuo (60° C., <1 mm) to afford 1.1 g (63%) of methyl3-(4-aminophthalimido)-3-(3,4-diethoxyphenyl)propionate as a yellowsolid: mp 143°-145° C.; ¹ H NMR (CDCl₃) δ 7.53-7.44 (m, 1 H); 6.99-6.78(m, 5 H), 6.52 (s, 2 H), 5.54 (dd, J=6.4, 9.5 Hz, 1 H), 4.05-3.89 (m, 4H), 3.66-3.48 (m, 1H), 3.55 (s, 3H), 3.35-3.20 (m, 1H), 1.37.1.2 (m, 6H); ¹³ C NMR (CDCl₃) δ 6 170.9, 168.1, 167.7, 155.1, 147.9, 147.8,134.1, 131.6, 125.1, 119.3, 116.8, 116.1, 113.2, 112.6, 106.9, 63.8,63.8, 51.5, 49.5, 14.7, 14.7; Anal. Calcd. for C₂₂ H₂₄ N₂ O₆.Theoretical: C, 64.07, H, 5.87, N, 6.79. Found: C, 63.97; H, 5.73; N,6.97.

EXAMPLE 99

A stirred mixture of phthalic dicarboxaldehyde (2.68 g, 20.0 mmol) and3-amino-3-(3-ethoxy4-methoxyphenyl)propionic acid (4.78 g, 20.0 mmol) inglacial acetic acid (50 mL) under nitrogen was heated to reflux for 5minutes. The reaction mixture was then allowed to cool to roomtemperature and was concentrated in vacuo to afford a yellow solid. Thecrude product was recryslallized twice from refluxing ethanol (150 mL).The resulting solid was then dried in vacuo (60° C., <1 mm) to afford4.4 g (62%) of3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid as awhite solid: mp 193.5°-194° C.; ¹ H NMR (DMSO-d₆) δ 12.40 (br s, 1 H),7.75-7.40 (m, 4 H), 7.05-6.85 (m, 3 H), 5.71 (m, 1 H), 4.51 (d, J=17.7Hz, 1 H), 4.11 (d, J=17.7 Hz, 1 H), 3.99 (m, 2 H), 3.73 (s, 3 H),3.25-3.02 (m, 2 H), 1.30 (t, J=6.9 Hz, 3 H); ¹³ C NMR (DMSO-d₆) δ 171.9,166.9, 148.5, 147.9, 141.7, 132.2, 131.6, 131.4, 127.9, 123.5, 122.9,119.3, 111.8, 63.7, 55.4, 51.2, 46.3, 36.8, 14.7; Anal. Calcd. for C₂₀H₂₁ NO₅. Theoretical: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.64; H,5.97; N, 3.92.

EXAMPLE 100

A mixture of3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy4-methoxyphenyl)propionic acid (12.6g, 35.4 mmol) and 1,1'-carbonyldiimidazole (5.97 g, 36.8 mmol), intetrahydrofuran (100 mL) was stirred for 1.5 hours at room temperature.To the solution was added ammonium hydroxide (7.5 mL, 112.5 mmol,28-30%) and stirring was continued for 20 minutes. The tetrahydrofuranwas removed in vacuo and the remaining residue was slurried in 100 mL ofwater for 30 minutes. The mixture was filtered and the white solid waswashed with water (150 mL), air dried and dried in vacuo (60° C., <1mm). The resulting solid was recrystallized form ethyl acetate (1.1 L)and was then dried in vacuo (60° C., <1 mm) to afford 9.61 g (77%) of3-(1-oxoisoindolin2-yl)-3-(3-ethoxy-4-methoxy-phenyl)propionamide as awhite solid: mp 169°-171.5; ¹ H NMR (DMSO-d₆) δ 7.75-7.40 (m, 5 H),7.05-6.80 (m, 4 H), 5.75 (m, 1 H), 4.56 (d, J=17.6 Hz, 1 H), 4.14 (d,J=17.6 Hz, 1 H), 3.98 (m, 2 H), 3.72 (s, 3 H), 2.93 (m, 2 H), 1.30 (t,J=6.9 Hz, 3H); ¹³ C NMR (DMSO-d₆) δ 171.2, 166.8, 148.3, 147.8, 141.6,132.2, 132.1, 131.2, 127.8, 123.4, 122.7, 119.1, 112.1, 111.7, 63.6,55.4, 51.3, 46.2, 37.8, 14.6; Anal. Calcd. for C₂₀ H₂₂ N₂ O₅.Theoretical: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.89; H, 6.31; N,7.83.

EXAMPLE 101

To an ice bath cooled solution of 50 mL of methanol was added acetylchloride (7.2 mL, 100 mmol). After stirring for 10 minutes3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid(6.00 g, 16.9 mmol) was added to the mixture. After 30 minutes the icebath was removed and the reaction was monitored by HPLC (Waters radialpak phenyl 8×100 mm column, 240 nm, 1.5 mL/min, 35/65 acetonitrile/0.1%phosphoric acid). After 4 hours the reaction had reached completion. Themethanol was removed in vacuo and the resulting residue was diluted with50 mL of methylene chloride. The mixture was extracted with aqueoussodium bicarbonate (50 mL) and brine. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo to afford a thickoil. Hexane (50 mL) and ether (5 mL) were added to the oil and themixture stirred overnight in an open flask. An additional 25 mL ofhexane were added to facilitate stirring. After 6 hours the slurry wasfiltered and the solid air dried and then dried in vacuo (60° C., <1 mm)to afford 5.45 g (87%) of methyl3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate as awhite solid: mp 78°-80° C.; ¹ H NMR (DMSO-d₆) δ 7.75-7.40 (m, 4 H),7.10-6.80 (m, 3 H), 5.72 (t, J=7.8 Hz, 1 H), 4.51 (d, J=17.7 Hz, 1 H),4.09 (d, J=17.7 Hz, 1 H), 3.97 (m, 2 H), 3.73 (s, 3 H), 3.55 (s, 3 H),3.24 (m, 2 H), 1.30 (m, 3 H); ¹³ C NMR (DMSO-d₆) δ 170.8, 166.8, 148.5,147.9, 141.6, 132.0, 131.3, 131.2, 127.8, 123.4, 122.8, 119.3, 112.2,111.8, 63.7, 55.4, 51.5, 51.0, 46.3, 36.2, 14.6; Anal. Calcd. for C₂₁H₂₃ NO₅. Theoretical: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.13; H,6.27; N, 3.70.

EXAMPLE 102

Tablets, each containing 50 mg of3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid, can be prepared in thefollowing manner:

Constituents (for 1000 tablets)

3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid . . . 50.0 g

lactose . . . 50.7 g

wheat starch . . . 7.5 g

polyethylene glycol 6000 . . . 5.0 g

talc . . . 5.0 g

magnesium stearate . . . 1.8 g

demineralized water . . . q.s.

The solid ingredients are first forced through a sieve of 0.6 mm meshwidth. The active ingredient, the lactose, the talc, the magnesiumstearate and half of the starch then are mixed. The other half of thestarch is suspended in 40 mL of water and this suspension is added to aboiling solution of the polyethylene glycol in 100 mL of water. Theresulting paste is added to the pulverulent substances and the mixtureis granulated, if necessary with the addition of water. The granulate isdried overnight at 35° C., forced through a sieve of 1.2 mm mesh widthand compressed to form tablets of approximately 6 mm diameter which areconcave on both sides.

EXAMPLE 103

Tablets, each containing 100 mg of3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide as active ingredient, canbe prepared in the following manner:

Constituents (for 1000 tablets)

3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide . . . 100.0 g

lactose . . . 100.0 g

wheat starch . . . 47.0 g

magnesium stearate . . . 3.0 g

All the solid ingredients are first forced through a sieve of 0.6 mmmesh width. The active ingredient, the lactose, the magnesium stearateand half of the starch then are mixed. The other half of the starch issuspended in 40 mL of water and this suspension is added to 100 mL ofboiling water. The resulting paste is added to the pulverulentsubstances and the mixture is granulated, if necessary with the additionof water. The granulate is dried overnight at 35° C., forced through asieve of 1.2 mm mesh width and compressed to form tablets ofapproximately 6 mm diameter which are concave on both sides.

EXAMPLE 104

Tablets for chewing, each containing 75 mg of3-(4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide as activeingredient, can be prepared in the following manner:

Composition (for 1000 tablets)

3-(4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide . . . 75.0 g

mannitol . . . 230 g

lactose . . . 150 g

talc . . . 21.0 g

glycine . . . 12.5 g

stearic acid . . . 10.0 g

saccharin . . . 1.5 g

5% gelatin solution . . . q.s.

All the solid ingredients are first forced through a sieve of 0.25 mmmesh width. The mannitol and the lactose are mixed, granulated with theaddition of gelatin solution, forced through a sieve of 2 mm mesh width,dried at 50° C. and again forced through a sieve of 1.7 mm mesh width.The active ingredient, the glycine and the saccharin are carefullymixed, the mannitol, the lactose granulate, the stearic acid and thetalc are added and the whole is mixed thoroughly and compressed to formtablets of approximately 10 mm diameter which are concave on both sidesand have a breaking groove on the upper side.

EXAMPLE 105

Tablets, each containing 10 mg of3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid as activeingredient, can be prepared in the following manner:

Composition (for 1000 tablets)

3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)

propionic acid . . . 10.0 g

lactose . . . 328.5 g

corn starch . . . 17.5 g

polyethylene glycol 6000 . . . 5.0 g

talc . . . 25.0 g

magnesium stearate . . . 4.0 g

demineralized water . . . q.s.

The solid ingredients are first forced through a sieve of 0.6 mm meshwidth. Then the active ingredient, lactose, talc, magnesium stearate andhalf of the starch are intimately mixed. The other half of the starch issuspended in 65 mL of water and this suspension is added to a boilingsolution of the polyethylene glycol in 260 mL of water. The resultingpaste is added to the pulverulent substances, and the whole is mixed andgranulated, if necessary with the addition of water. The granulate isdried overnight at 35° C., forced through a sieve of 1.2 mm mesh widthand compressed to form tablets of approximately 10 mm diameter which areconcave on both sides and have a breaking notch on the upper side.

EXAMPLE 106

Gelatin dry-filled capsules, each containing 100 mg of3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide as activeingredient, can be prepared in the following manner:

Composition (for 1000 capsules)

3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide . . . 100.0g

microcrystalline cellulose . . . 30.0 g

sodium lauryl sulphate . . . 2.0 g

magnesium stearate . . . 8.0 g

The sodium lauryl sulphate is sieved into the active ingredient througha sieve of 0.2 mm mesh width and the two components are intimately mixedfor 10 minutes. The microcrystalline cellulose is then added through asieve of 0.9 mm mesh width and the whole is again intimately mixed for10 minutes. Finally, the magnesium stearate is added through a sieve of0.8 mm width and, after mixing for a further 3 minutes, the mixture isintroduced in portions of 140 mg each into size 0 (elongated) gelatindry-fill capsules.

EXAMPLE 107

A 0.2% injection or infusion solution can be prepared, for example, inthe following manner:

3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acidsodium salt . . . 5.0 g

sodium chloride . . . 22.5 g

phosphate buffer pH 7.4 . . . 300.0 g

demineralized water q.s . . . 2500.0 mL

The active ingredient is dissolved in 1000 mL of water and filteredthrough a microfilter. The buffer solution is added and the whole ismade up to 2500 mL with water. To prepare dosage unit forms, portions of1.0 or 2.5 mL each are introduced into glass ampoules (each containingrespectively 2.0 or 5.0 mg of active ingredient).

What is claimed is:
 1. A compound of the formula: ##STR11## in which: nhas a value of 1, 2, or 3;R⁵ is vic-naphthylene unsubstituted orsubstituted with 1 to 4 substituents each selected independently fromthe group consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, and halo; R⁶ is CO or CH₂ ; R⁷ is (i) phenyl or phenylsubstituted with one or more substituents each selected independently ofthe other from the group consisting of nitro, cyano, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy,carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to10 carbon atoms, and halo, (ii) benzyl unsubstituted or substituted with1 to 3 substituents selected from the group consisting of nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) naphthyl, and(iv) benzyloxy; R¹² is --OH, alkoxy of 1 to 12 carbon atoms, or##STR12## R^(8') is hydrogen or alkyl of 1 to 10 carbon atoms; andR^(9') is hydrogen, alkyl of 1 to 10 carbon atoms, --COR¹⁰, or --SO₂ R¹⁰in which R¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.
 2. Acompound according to claim 1 in which R¹² is ##STR13## R^(8') andR^(9') are as therein defined.
 3. A compound according to claim 2 inwhich R⁵ is vic-naphthylene, R⁷ is phenyl monosubstituted ordisubstituted with nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, or halo, n is 1, and each of R^(8') and R^(9') is hydrogen.
 4. Acompound according to claim 3 in which R⁷ is phenyl substituted with 1to 3 alkoxy groups of 1 to 4 carbon atoms.
 5. A compound according toclaim 4 wherein R⁷ is phenyl substituted with alkoxy of 1 to 4 carbonatoms in the 3- and 4-positions.
 6. A compound according to claim 5 inwhich R⁷ is phenyl substituted with methoxy in the 4-position andmethoxy, ethoxy, propoxy, or isopropoxy in the 3-position.
 7. A compoundaccording to claim claim 1 in which R¹² is --OH.
 8. A compound accordingto claim 7 in which R⁵ is vic-naphthylene, R⁷ is phenyl monosubstitutedor disubstituted with nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, and halo, and n is
 1. 9. A compound according to claim 8 in whichR⁷ is phenyl substituted with 1 to 3 alkoxy groups of 1 to 4 carbonatoms.
 10. A compound according to claim 9 wherein R⁷ is phenylsubstituted with alkoxy of 1 to 4 carbon atoms in the 3- and4-positions.
 11. A compound according to claim 10 in which R⁷ is phenylsubstituted with methoxy in the 4-position and methoxy, ethoxy, propoxy,or isopropoxy in the 3-position.
 12. A compound according to claim 1 inwhich R¹² is alkoxy of 1 to 12 carbon atoms.
 13. A compound according toclaim 12 in which R⁵ is vic-naphthylene, R⁷ is phenyl monosubstituted ordisubstituted with nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, or halo, n is 1, and R¹² is alkoxy of 1 to 6 carbon atoms.
 14. Acompound according to claim 13 in which R⁷ is phenyl substituted with 1to 3 alkoxy groups of 1 to 4 carbon atoms.
 15. A compound according toclaim 14 wherein R⁷ is phenyl substituted with alkoxy of 1 to 4 carbonatoms in the 3- and 4-positions.
 16. A compound according to claim 15 inwhich R⁷ is phenyl substituted with methoxy in the 4-position andmethoxy, ethoxy, propoxy, or isopropoxy in the 3-position.
 17. Acompound according to claim 1 in which R⁵ is vic-naphthylene, R⁶ is CH₂; R⁷ is unsubstituted phenyl or phenyl monosubstituted or disubstitutedwith alkoxy of 1 to 10 carbon atoms, or halo, R¹² is --OH, methoxy,ethoxy, or amino.
 18. A compound according to claim 17 in which R⁷ isphenyl.
 19. A compound according to claim 17 in which R⁷ is4-methoxyphenyl.
 20. A compound according to claim 17 in which R⁷ is3,4-dimethoxyphenyl.
 21. A compound according to claim 17 in which R⁷ is3-ethoxy-4-methoxyphenyl.
 22. A compound according to claim 17 in whichR⁷ is 3,4-diethoxyphenyl.
 23. A compound according to claim 17 in whichR⁷ is 3-propoxy-4-methoxyphenyl.
 24. A compound according to claim 17 inwhich R⁷ is 3-butoxy-4-methoxyphenyl.
 25. A compound according to claim1 in which R⁵ is vic-naphthylene, R⁶ is CO; R⁷ is unsubstituted phenylor phenyl monosubstituted or disubstituted with alkoxy of 1 to 10 carbonatoms, or halo, R¹² is --OH, methoxy, ethoxy, or amino.
 26. A compoundaccording to claim 25 in which R⁷ is phenyl.
 27. A compound according toclaim 25 in which R⁷ is 4-methoxyphenyl.
 28. A compound according toclaim 25 in which R⁷ is 3,4-dimethoxyphenyl.
 29. A compound according toclaim 25 in which R⁷ is 3-ethoxy-4-methoxyphenyl.
 30. A compoundaccording to claim 25 in which R⁷ is 3-propoxy-4-methoxyphenyl.
 31. Acompound according to claim 25 in which R⁷ is 3-butoxy-4-methoxyphenyl.32. The method of reducing levels of TNFα in a mammal which comprisesadministering thereto an effective amount of a compound according toclaim
 1. 33. A pharmaceutical composition comprising a quantity of acompound according to claim 1 sufficient upon administration in a singleor multiple dose regimen to reduce levels of TNFα in a mammal incombination with a carrier.